Science.gov

Sample records for congenital myotonic dystrophy

  1. Myotonic Dystrophy and Facioscapulohumeral Muscular Dystrophy Registry

    ClinicalTrials.gov

    2016-08-26

    Myotonic Dystrophy; Facioscapulohumeral Muscular Dystrophy; Muscular Dystrophy; Myotonic Dystrophy Type 1; Myotonic Dystrophy Type 2; Congenital Myotonic Dystrophy; PROMM (Proximal Myotonic Myopathy); Steinert's Disease; Myotonic Muscular Dystrophy

  2. Congenital myotonic dystrophy in Britain. I. Clinical aspects.

    PubMed Central

    Harper, P S

    1975-01-01

    A clinical and genetic study of congenital myotonic dystrophy in Britain has been carried out in 70 patients from 54 sibships. The clinical aspects are analysed here, and the existence of a syndrome clinically distinct from myotonic dystrophy of later onset is confirmed. Characteristic features included neonatal hypotonia, motor and mental retardation, and facial diplegia. A high incidence of talipes occurs at birth together with hydramnios and reduced fetal movements during pregnancy, factors suggesting prenatal onset of the disorder in many cases. Prolonged survival is the rule after infancy, but the occurrence of numerous neonatal deaths in the sibships suggests the existence of unrecognized cases dying in the neonatal period. PMID:1101835

  3. Myotonic Muscular Dystrophy

    MedlinePlus

    ... a Difference How to Get Involved Donate Myotonic Muscular Dystrophy (MMD) Share print email share facebook twitter google plus linkedin Myotonic Muscular Dystrophy (MMD) What is myotonic muscular dystrophy (MMD)? Myotonic ...

  4. Myotonic Dystrophy

    PubMed Central

    Thornton, Charles A.

    2014-01-01

    Myotonic dystrophy (dystrophia myotonica, DM) is one of the most common lethal monogenic disorders in populations of European descent. Myotonic dystrophy type 1 (DM1) was first described over a century ago. DM1 is caused by expansion of a CTG triplet repeat in the 3' non-coding region of DMPK, the gene encoding the DM protein kinase. More recently a second form of the disease, myotonic dystrophy type 2 (DM2) was recognized, which results from repeat expansion in a different gene. The DM2 expansion involves a CCTG repeat in the first intron of Zinc Finger 9 (ZNF9). Both disorders have autosomal dominant inheritance and multisystem features, including myotonic myopathy, cataract, and cardiac conduction disease. Studies suggest that the shared clinical features of DM1 and DM2 involve a novel genetic mechanism in which repetitive RNA exerts a toxic effect. The RNA toxicity stems from the expanded repeat in the transcripts from the mutant DM alleles. This chapter will review the clinical presentation and pathophysiology of DM, and discuss current management and future potential for developing targeted therapies. PMID:25037086

  5. The natural history of congenital myotonic dystrophy: mortality and long term clinical aspects.

    PubMed Central

    Reardon, W; Newcombe, R; Fenton, I; Sibert, J; Harper, P S

    1993-01-01

    Although the genetic basis of the congenital form of myotonic dystrophy has recently been clarified, data as to outcome in terms of life expectancy and morbidity are scanty. Life table data based on a cohort of 115 patients with a confirmed diagnosis of congenital myotonic dystrophy are presented. The data suggest a 25% chance of death before 18 months of age and a 50% chance of survival into the mid-30s. The profile of disease and complications among survivors is also charted. PMID:8481038

  6. Congenital and childhood myotonic dystrophy: Current aspects of disease and future directions.

    PubMed

    Ho, Genevieve; Cardamone, Michael; Farrar, Michelle

    2015-11-01

    Myotonic dystrophy type 1 (DM1) is multisystem disease arising from mutant CTG expansion in the non-translating region of the dystrophia myotonica protein kinase gene. While DM1 is the most common adult muscular dystrophy, with a worldwide prevalence of one in eight thousand, age of onset varies from before birth to adulthood. There is a broad spectrum of clinical severity, ranging from mild to severe, which correlates with number of DNA repeats. Importantly, the early clinical manifestations and management in congenital and childhood DM1 differ from classic adult DM1. In neonates and children, DM1 predominantly affects muscle strength, cognition, respiratory, central nervous and gastrointestinal systems. Sleep disorders are often under recognised yet a significant morbidity. No effective disease modifying treatment is currently available and neonates and children with DM1 may experience severe physical and intellectual disability, which may be life limiting in the most severe forms. Management is currently supportive, incorporating regular surveillance and treatment of manifestations. Novel therapies, which target the gene and the pathogenic mechanism of abnormal splicing are emerging. Genetic counselling is critical in this autosomal dominant genetic disease with variable penetrance and potential maternal anticipation, as is assisting with family planning and undertaking cascade testing to instigate health surveillance in affected family members. This review incorporates discussion of the clinical manifestations and management of congenital and childhood DM1, with a particular focus on hypersomnolence and sleep disorders. In addition, the molecular genetics, mechanisms of disease pathogenesis and development of novel treatment strategies in DM1 will be summarised. PMID:26566479

  7. Congenital and childhood myotonic dystrophy: Current aspects of disease and future directions

    PubMed Central

    Ho, Genevieve; Cardamone, Michael; Farrar, Michelle

    2015-01-01

    Myotonic dystrophy type 1 (DM1) is multisystem disease arising from mutant CTG expansion in the non-translating region of the dystrophia myotonica protein kinase gene. While DM1 is the most common adult muscular dystrophy, with a worldwide prevalence of one in eight thousand, age of onset varies from before birth to adulthood. There is a broad spectrum of clinical severity, ranging from mild to severe, which correlates with number of DNA repeats. Importantly, the early clinical manifestations and management in congenital and childhood DM1 differ from classic adult DM1. In neonates and children, DM1 predominantly affects muscle strength, cognition, respiratory, central nervous and gastrointestinal systems. Sleep disorders are often under recognised yet a significant morbidity. No effective disease modifying treatment is currently available and neonates and children with DM1 may experience severe physical and intellectual disability, which may be life limiting in the most severe forms. Management is currently supportive, incorporating regular surveillance and treatment of manifestations. Novel therapies, which target the gene and the pathogenic mechanism of abnormal splicing are emerging. Genetic counselling is critical in this autosomal dominant genetic disease with variable penetrance and potential maternal anticipation, as is assisting with family planning and undertaking cascade testing to instigate health surveillance in affected family members. This review incorporates discussion of the clinical manifestations and management of congenital and childhood DM1, with a particular focus on hypersomnolence and sleep disorders. In addition, the molecular genetics, mechanisms of disease pathogenesis and development of novel treatment strategies in DM1 will be summarised. PMID:26566479

  8. Hypothalamic hypogonadism in myotonic dystrophy.

    PubMed

    Ulloa-Aguirre, A; Larrea, F; Shkurovich, M

    1981-06-01

    Hypothalamic-pituitary-ovarian axis function was assessed in a postpubertal female patient with myotonic dystrophy and secondary amenorrhea. The results suggested a hypothalamic basis for the amenorrhea, confirming previous reports regarding the nature of gonadal failure in women with this multisystemic disorder.

  9. Cognition and Adaptive Skills in Myotonic Dystrophy Type 1: A Study of 55 Individuals with Congenital and Childhood Forms

    ERIC Educational Resources Information Center

    Ekstrom, Anne-Berit; Hakenas-Plate, Louise; Tulinius, Mar; Wentz, Elisabet

    2009-01-01

    Aims: To investigate cognitive abilities and adaptive skills in children and adolescents with myotonic dystrophy type 1 (DM1) and correlate the findings to the cytosine-thymine-guanine (CTG) repeat expansion size. Method: Cognitive level was assessed in 55 children and adolescents with DM1 (31 males, 24 females; mean age 12y 1mo, SD 5y 1mo; range…

  10. Hypothesis: neoplasms in myotonic dystrophy

    PubMed Central

    Hilbert, James E.; Martens, William; Thornton, Charles A.; Moxley, Richard T.; Greene, Mark H.

    2011-01-01

    Tumorigenesis is a multi-step process due to an accumulation of genetic mutations in multiple genes in diverse pathways which ultimately lead to loss of control over cell growth. It is well known that inheritance of rare germline mutations in genes involved in tumorigenesis pathways confer high lifetime risk of neoplasia in affected individuals. Furthermore, a substantial number of multiple malformation syndromes include cancer susceptibility in their phenotype. Studies of the mechanisms underlying these inherited syndromes have added to the understanding of both normal development and the pathophysiology of carcinogenesis. Myotonic dystrophy (DM) represents a group of autosomal dominant, multisystemic diseases that share the clinical features of myotonia, muscle weakness, and early-onset cataracts. Myotonic dystrophy type 1 (DM1) and myotonic dystrophy type 2 (DM2) result from unstable nucleotide repeat expansions in their respective genes. There have been multiple reports of tumors in individuals with DM, most commonly benign calcifying cutaneous tumors known as pilomatricomas. We provide a summary of the tumors reported in DM and a hypothesis for a possible mechanism of tumorigenesis. We hope to stimulate further study into the potential role of DM genes in tumorigenesis, and help define DM pathogenesis, and facilitate developing novel treatment modalities. PMID:19642006

  11. Risk estimates for neonatal myotonic dystrophy.

    PubMed Central

    Glånz, A; Fråser, F C

    1984-01-01

    Children who inherit the autosomal dominant gene for myotonic dystrophy from their mother rather than their father may develop the severe neonatal type rather than the late onset type. The families of 22 neonatal type probands and 59 late onset type probands were studied to determine the risk of occurrence and recurrence of the neonatal type. The frequency of the neonatal type in sibs of neonatal type probands was 29%, or 37% if cases of neonatal deaths are counted as affected. This is significantly higher than the 6% of the neonatal type found in the offspring of affected women not ascertained through a child with the neonatal type. These data suggest that certain women carrying the gene for myotonic dystrophy are predisposed to have children affected with the neonatal type rather than the late onset type. The female near relatives of these women do not seem to share this predisposition. The data should be useful for genetic counseling. PMID:6748014

  12. Hypothalamic-pituitary function in myotonic dystrophy.

    PubMed

    Mahler, C; Parizel, G

    1982-01-01

    Function of the hypothalamic-pituitary axis was investigated in seven patients with myotonic dystrophy (MD). HGH and ACTH secretion were normal. TSH response to TRH was impaired in about half the cases, without concomitant thyroid dysfunction. LH and FSH levels were often elevated, with inconsistent response to LH-RH stimulation, Gonadotrophin disturbances in MD have previously been attributed to a primary gonadal lesion, characteristically seen in this disease. High prolactin levels in six of our seven patients however suggest that gonadal failure may be also be due to hyperprolactinemia through the direct anti-gonadal effect of prolactin and its interference with hypothalamic-pituitary regulation of gonadotrophin secretion.

  13. Therapeutics Development in Myotonic Dystrophy Type I

    PubMed Central

    Foff, Erin Pennock; Mahadevan, Mani S.

    2011-01-01

    Myotonic dystrophy (DM1), the most common adult muscular dystrophy, is a multi-system, autosomal dominant genetic disorder caused by an expanded CTG repeat that leads to nuclear retention of a mutant RNA and subsequent RNA toxicity. Significant insights into the molecular mechanisms of RNA toxicity have led to the surprising possibility that treating DM1 is a viable prospect. In this review, we briefly present the clinical picture in DM1, and describe how the research in understanding the pathogenesis of RNA toxicity in DM1 has led to targeted approaches to therapeutic development at various steps in the pathogenesis of the disease. We discuss the promise and current limitations of each with an emphasis on RNA-based therapeutics and small molecules. We conclude with a discussion of the unmet need for clinical tools and outcome measures that are essential prerequisites to proceed in evaluating these potential therapies in clinical trials. PMID:21607985

  14. Diagnostic Odyssey of Patients with Myotonic Dystrophy

    PubMed Central

    Hilbert, James E.; Ashizawa, Tetsuo; Day, John W.; Luebbe, Elizabeth A.; Martens, William B.; McDermott, Michael P.; Tawil, Rabi; Thornton, Charles A.; Moxley, Richard T.

    2013-01-01

    The onset and symptoms of the myotonic dystrophies are diverse, complicating their diagnoses and limiting a comprehensive approach to their clinical care. This report analyzes the diagnostic delay (time from onset of first symptom to diagnosis) in a large sample of myotonic dystrophy (DM) patients enrolled in the US National Registry [679 DM type 1 (DM1) and 135 DM type 2 (DM2) patients]. Age of onset averaged 34.0 ± 14.1 years in DM2 patients compared to 26.1 ± 13.2 years in DM1 (p<0.0001). The most common initial symptom in DM2 patients was leg weakness (32.6%) compared to grip myotonia in DM1 (38.3%). Pain was reported as the first symptom in 11.1% of DM2 and 3.0% of DM1 patients (p<0.0001). Reaching the correct diagnosis in DM2 took 14 years on average (double the time compared to DM1) and a significantly higher percentage of patients underwent extended workup including electromyography, muscle biopsies, and finally genetic testing. DM patients who were index cases experienced similar diagnostic delays to non-index cases of DM. Further evaluation of how to shorten these diagnostic delays and limit their impact on burdens of disease, family planning, and symptom management is needed. PMID:23807151

  15. Anesthetic management of a myotonic dystrophy patient with paraganglionoma.

    PubMed

    Subramaniam, Ashwin; Grauer, Robert; Beilby, David; Tiruvoipati, Ravindranath

    2016-11-01

    Myotonic dystrophy (DM), though rare, can significantly complicate anesthesia due to muscular and extra-muscular involvement. When this condition is compounded by a pheochromocytoma, anesthetizing such patients becomes extra challenging. We present a case report of a 61-year-old lady with congenital DM, with the whole gamut of associated features, was diagnosed with a noradrenaline secreting paraganglionoma following investigation of refractory hypertension. We anesthetized her for an open resection of the lesion. The conduct of anesthesia and recovery of this patient is described. Our experience suggests that anesthetizing these patients though challenging can be safely managed with relaxant general anesthesia and epidural analgesia with meticulous care pre, intra and post-surgical intervention. PMID:27687340

  16. Gastrointestinal manifestations in myotonic muscular dystrophy

    PubMed Central

    Bellini, Massimo; Biagi, Sonia; Stasi, Cristina; Costa, Francesco; Mumolo, Maria Gloria; Ricchiuti, Angelo; Marchi, Santino

    2006-01-01

    Myotonic dystrophy (MD) is characterized by myotonic phenomena and progressive muscular weakness. Involvement of the gastrointestinal tract is frequent and may occur at any level. The clinical manifestations have previously been attributed to motility disorders caused by smooth muscle damage, but histologic evidence of alterations has been scarce and conflicting. A neural factor has also been hypothesized. In the upper digestive tract, dysphagia, heartburn, regurgitation and dyspepsia are the most common complaints, while in the lower tract, abdominal pain, bloating and changes in bowel habits are often reported. Digestive symptoms may be the first sign of dystrophic disease and may precede the musculo-skeletal features. The impairment of gastrointestinal function may be sometimes so gradual that the patients adapt to it with little awareness of symptoms. In such cases routine endoscopic and ultrasonographic evaluations are not sufficient and targeted techniques (electrogastrography, manometry, electromyography, functional ultrasonography, scintigraphy, etc.) are needed. There is a low correlation between the degree of skeletal muscle involvement and the presence and severity of gastrointestinal disturbances whereas a positive correlation with the duration of the skeletal muscle disease has been reported. The drugs recommended for treating the gastrointestinal complaints such as prokinetic, anti-dyspeptic drugs and laxatives, are mainly aimed at correcting the motility disorders. Gastrointestinal involvement in MD remains a complex and intriguing condition since many important problems are still unsolved. Further studies concentrating on genetic aspects, early diagnostic techniques and the development of new therapeutic strategies are needed to improve our management of the gastrointestinal manifestations of MD. PMID:16609987

  17. Hyperkalaemia and selective hypoaldosteronism in myotonic dystrophy.

    PubMed

    Misra, Dolly; DeSilva, Shari; Fellerman, Herbert; Dufour, D Robert; Streeten, David H P; Nylen, Eric S

    2002-02-01

    Myotonic dystrophy (MyD) is a common genetic neuromuscular disorder in which chromosome 19 gives rise to an abnormal expansion of CTG-trinucleotide repeats. MyD is a highly variable multisystem disorder with muscular and nonmuscular abnormalities. Increasingly, endocrine abnormalities, such as gonadal, pancreatic, and adrenal dysfunction are being uncovered. Herein we present three unrelated cases with MyD with abnormally elevated serum potassium; 2 of the 3 cases presented clinically with cardiac dysrhythmias. Hyperkalaemic conditions such as renal failure, cortisol deficiency, pseudohyperkalaemia, and hyperkalaemic periodic paralysis were excluded. Further endocrine evaluation revealed baseline hypoaldosteronism associated with elevated renin activity. Perturbation of the renin-angiotensin-aldosterone system resulted in appropriately enhanced renin activity but with a subnormal aldosterone response, which appeared to be due to adrenal hyporesponsiveness. The treatment of all cases with fludrocortisone was without effect. Whether the apparent mineralocorticoid abnormality in MyD is due to associated hormonal perturbations (i.e. excessive ACTH responsiveness. elevated cytokines, elevated atrial natriuretic hormone, etc.), adrenal atrophy, and/or a manifestation of the underlying kinase dysfunction is uncertain, but merits further evaluation in view of the clinical consequence of hyperkalaemia.

  18. Psychiatric and Cognitive Phenotype of Childhood Myotonic Dystrophy Type 1

    ERIC Educational Resources Information Center

    Douniol, Marie; Jacquette, Aurelia; Cohen, David; Bodeau, Nicolas; Rachidi, Linda; Angeard, Nathalie; Cuisset, Jean-Marie; Vallee, Louis; Eymard, Bruno; Plaza, Monique; Heron, Delphine; Guile, Jean-Marc

    2012-01-01

    Aim: To investigate the psychiatric and cognitive phenotype in young individuals with the childhood form of myotonic dystrophy type 1 (DM1). Method: Twenty-eight individuals (15 females, 13 males) with childhood DM1 (mean age 17y, SD 4.6, range 7-24y) were assessed using standardized instruments and cognitive testing of general intelligence,…

  19. Chronic Pain in Persons With Myotonic Dystrophy and Facioscapulohumeral Dystrophy

    PubMed Central

    Jensen, Mark P.; Hoffman, Amy J.; Stoelb, Brenda L.; Abresch, Richard T.; Carter, Gregory T.; McDonald, Craig M.

    2009-01-01

    Objective To determine the nature and scope of pain in working-aged adults with myotonic muscular dystrophy (MMD) and facioscapulohumeral muscular dystrophy (FSHD). Design Retrospective, cross-sectional survey. Setting Community-based survey. Participants Convenience sample of subjects with MMD and FSHD. Interventions Not applicable. Main Outcome Measures Overall intensity and duration of pain, pain inference, pain sites, pain treatments, and relief provided by pain treatments. Results More subjects with FSHD (82%) than with MMD (64%) reported pain. The most frequently reported pain sites for both diagnostic groups were lower back (66% MMD, 74% FSHD) and legs (60% MMD, 72% FSHD). Significant differences in pain intensity were found between the diagnostic groups in the hands, legs, knees, ankles, and feet, with patients with MMD reporting greater pain intensity at these sites than patients with FSHD. Age was related to the onset of pain (participants reporting pain were younger than those not reporting pain in the FSHD sample), but pain severity was not significantly associated with age in those reporting pain. Respondents with both diagnoses that reported mobility limitations and used assistive devices (eg, wheelchair, cane) reported more pain severity than those with mobility limitations who did not use assistive devices, who, in turn, reported more pain severity than respondents who reported no mobility limitations at all. The treatments that were reported to provide the greatest pain relief were not necessarily those that were the most frequently tried or still used. Conclusions The findings indicate that pain is a more common problem in persons with FSHD than in persons with MMD, although it is common in both populations. In addition, these pain problems are chronic, underscoring the need to identify and provide effective pain treatments for patients with these neuromuscular diseases. PMID:18226657

  20. The brain in myotonic dystrophy 1 and 2: evidence for a predominant white matter disease.

    PubMed

    Minnerop, Martina; Weber, Bernd; Schoene-Bake, Jan-Christoph; Roeske, Sandra; Mirbach, Sandra; Anspach, Christian; Schneider-Gold, Christiane; Betz, Regina C; Helmstaedter, Christoph; Tittgemeyer, Marc; Klockgether, Thomas; Kornblum, Cornelia

    2011-12-01

    Myotonic dystrophy types 1 and 2 are progressive multisystemic disorders with potential brain involvement. We compared 22 myotonic dystrophy type 1 and 22 myotonic dystrophy type 2 clinically and neuropsychologically well-characterized patients and a corresponding healthy control group using structural brain magnetic resonance imaging at 3 T (T(1)/T(2)/diffusion-weighted). Voxel-based morphometry and diffusion tensor imaging with tract-based spatial statistics were applied for voxel-wise analysis of cerebral grey and white matter affection (P(corrected) < 0.05). We further examined the association of structural brain changes with clinical and neuropsychological data. White matter lesions rated visually were more prevalent and severe in myotonic dystrophy type 1 compared with controls, with frontal white matter most prominently affected in both disorders, and temporal lesions restricted to myotonic dystrophy type 1. Voxel-based morphometry analyses demonstrated extensive white matter involvement in all cerebral lobes, brainstem and corpus callosum in myotonic dystrophy types 1 and 2, while grey matter decrease (cortical areas, thalamus, putamen) was restricted to myotonic dystrophy type 1. Accordingly, we found more prominent white matter affection in myotonic dystrophy type 1 than myotonic dystrophy type 2 by diffusion tensor imaging. Association fibres throughout the whole brain, limbic system fibre tracts, the callosal body and projection fibres (e.g. internal/external capsules) were affected in myotonic dystrophy types 1 and 2. Central motor pathways were exclusively impaired in myotonic dystrophy type 1. We found mild executive and attentional deficits in our patients when neuropsychological tests were corrected for manual motor dysfunctioning. Regression analyses revealed associations of white matter affection with several clinical parameters in both disease entities, but not with neuropsychological performance. We showed that depressed mood and fatigue were

  1. [Myotonic dystrophy and bundle-branch re-entrant tachycardia].

    PubMed

    Ramírez, Carlos J; Rodríguez, Diego A; Velasco, Víctor M; Rosas, Fernando

    2002-10-01

    We report the case of a 37-year-old man diagnosed with myotonic dystrophy who presented atrial fibrillation with high ventricular rate. While being treated with amiodarone, he suffered cardiac arrest. The electrophysiological study disclosed bundle-branch reentrant ventricular tachycardia and ventricular fibrillation. Catheter ablation of the right bundle branch was performed and a bicameral defibrillator was implanted. The mechanisms and treatment of arrhythmias in these patients are discussed. PMID:12383397

  2. Sleep-Wake Cycle and Daytime Sleepiness in the Myotonic Dystrophies.

    PubMed

    Romigi, A; Albanese, M; Liguori, C; Placidi, F; Marciani, M G; Massa, R

    2013-01-01

    Myotonic dystrophy is the most common type of muscular dystrophy in adults and is characterized by progressive myopathy, myotonia, and multiorgan involvement. Two genetically distinct entities have been identified, myotonic dystrophy type 1 (DM1 or Steinert's Disease) and myotonic dystrophy type 2 (DM2). Myotonic dystrophies are strongly associated with sleep dysfunction. Sleep disturbances in DM1 are common and include sleep-disordered breathing (SDB), periodic limb movements (PLMS), central hypersomnia, and REM sleep dysregulation (high REM density and narcoleptic-like phenotype). Interestingly, drowsiness in DM1 seems to be due to a central dysfunction of sleep-wake regulation more than SDB. To date, little is known regarding the occurrence of sleep disorders in DM2. SDB (obstructive and central apnoea), REM sleep without atonia, and restless legs syndrome have been described. Further polysomnographic, controlled studies are strongly needed, particularly in DM2, in order to clarify the role of sleep disorders in the myotonic dystrophies.

  3. NIH study shows increased risk for two types of myotonic muscular dystrophy

    Cancer.gov

    Adults with a form of muscular dystrophy called myotonic muscular dystrophy (MMD) may be at increased risk of developing cancer, according to a study by investigators at the National Cancer Institute (NCI), part of the National Institutes of Health.

  4. Effect of maternal transmissions on clinical manifestations of myotonic dystrophy

    SciTech Connect

    Eguchi, I.; Koike, R.; Onodera, O.

    1994-09-01

    The mutation of myotonic dystrophy (DM) has been identified as unstable expansions of trinucleotide CTG repeat, located on chromosome 19q13-3. Although previous investigations have emphasized the strong association of the sizes of the CTG repeat with ages of onset as well as the clinical manifestations, effects of the paternal or maternal transmissions other than CTG repeats on the clinical manifestations in DM have not been evaluated in detail. To investigate how parental transmission affect the DM phenotype, we analyzed 15 cases of paternal transmission and 25 cases of maternal transmission. We have classified DM patients into 4 clinical grades. As in accordance with previous reports, there is a good correlation on sizes of the CTG repeat with their clinical features. The sizes of the CTG repeat in congenital DM patients (4.13{plus_minus}0.221 kbp) (Mean {plus_minus}SEM), who inherited mutant genes from their mothers, were not significantly larger than those of non-congenital DM patients (3.65 {plus_minus}0.36 kbp). As it has been well established that congenital DM patients are born to affected mothers, we investigated to see if there are any parental bias on the clinical manifestations in non-congenital DM. We classified each case into 4 classes depending on the size ranges of the CTG repeat (0 to 1.5 kbp, 1.5 to 3.0 kbp, 3.0 to 4.5 kbp, 4.5 kbp<). In each group of the size ranges of the CTG repeat, the distribution of cases among grades I to III were compared between paternally and maternally transmitted cases. There were statistically significant differences in the distributions of cases among grades I to III for the size ranges of 3 to 4.5 kbp expansions (p<0.01) and over 4.5 kbp expansions (p<0.05) on {chi}{sup 2} test, respectively. The results revealed that maternally transmitted cases tend to show severe phenotypes compared to paternally transmitted ones even if they have similar sizes of CTG repeat.

  5. Warming up Improves Speech Production in Patients with Adult Onset Myotonic Dystrophy

    ERIC Educational Resources Information Center

    de Swart, B.J.M.; van Engelen, B.G.M.; Maassen, B.A.M.

    2007-01-01

    This investigation was conducted to study whether warming up decreases myotonia (muscle stiffness) during speech production or causes adverse effects due to fatigue or exhaustion caused by intensive speech activity in patients with adult onset myotonic dystrophy. Thirty patients with adult onset myotonic dystrophy (MD) and ten healthy controls…

  6. Vascular adrenergic receptor responses in skeletal muscle in myotonic dystrophy

    SciTech Connect

    Mechler, F.; Mastaglia, F.L.

    1981-02-01

    The pharmacological responses of vascular adrenergic receptors to intravenously administered epinephrine, phentolamine, and propranolol were assessed by measuring muscle blood flow (MBF) changes in the tibialis anterior muscle using the xenon 133 clearance technique and were compared in 8 normal subjects and 11 patients with myotonic dystrophy. In cases with advanced involvement of the muscle, the resting MBF was reduced and was not significantly altered by epinephrine before or after alpha- or beta-receptor blockade. In patients in whom the tibialis anterior muscle was normal or only minimally affected clinically, a paradoxical reduction in the epinephrine-induced increase in MBF was found after alpha blockade by phentolamine, and the epinephrine-induced MBF increase was not completely blocked by propranolol as in the normal subjects. These findings point to functional alteration in the properties of vascular adrenergic receptors in muscle in myotonic dystrophy. While this may be another manifestation of a widespread cell membrane defect in the disease, the possibility that the changes are secondary to the myotonic state cannot be excluded.

  7. Congenital myopathies and muscular dystrophies.

    PubMed

    Gilbreath, Heather R; Castro, Diana; Iannaccone, Susan T

    2014-08-01

    The congenital muscular dystrophies (CMD) and myopathies (CM) are a diverse group of diseases that share features such as early onset of symptoms (in the first year of life), genetic causes, and high risks for restrictive lung disease and orthopedic deformities. Understanding for disease mechanism is available and a fairly well-structured genotype-phenotype correlation for all the CMDs and CMs is now available. To best illustrate the clinical spectrum and diagnostic algorithm for these diseases, this article presents 5 cases, including Ullrich congenital muscular dystrophy, nemaline myopathy, centronuclear myopathy, merosin deficiency congenital muscular dystrophy, and core myopathy.

  8. Congenital myopathies and muscular dystrophies.

    PubMed

    Gilbreath, Heather R; Castro, Diana; Iannaccone, Susan T

    2014-08-01

    The congenital muscular dystrophies (CMD) and myopathies (CM) are a diverse group of diseases that share features such as early onset of symptoms (in the first year of life), genetic causes, and high risks for restrictive lung disease and orthopedic deformities. Understanding for disease mechanism is available and a fairly well-structured genotype-phenotype correlation for all the CMDs and CMs is now available. To best illustrate the clinical spectrum and diagnostic algorithm for these diseases, this article presents 5 cases, including Ullrich congenital muscular dystrophy, nemaline myopathy, centronuclear myopathy, merosin deficiency congenital muscular dystrophy, and core myopathy. PMID:25037085

  9. Segmental myofiber necrosis in myotonic dystrophy - An immunoperoxidase study of immunoglobulins in skeletal muscle.

    PubMed Central

    Silver, M. M.; Banerjee, D.; Hudson, A. J.

    1983-01-01

    Because serum immunoglobulin G levels are low in patients with myotonic dystrophy, it was hypothesized that it might be catabolized within abnormal muscle fibers. Accordingly, immunohistochemical stains for immunoglobulins were performed on muscle sections derived at biopsy or autopsy from patients with myotonic dystrophy, other forms of muscular dystrophy, nondystrophic muscle disease, or normal muscle. Positive staining for immunoglobulins was found only in necrotic segments of myofibers (in 7 of 19 dystrophic and 6 of 27 nondystrophic subjects), and it is believed that the staining was due to nonspecific diffusion. However, staining reactions distinguished between incipient necrosis and artifactual contraction bands and allowed us to study segmental myofiber necrosis, comparing its frequency in the various muscle diseases. Segmental myofiber necrosis was present in 4 of 16 cases of myotonic dystrophy. The relevance of this finding to the clinical and morphologic features of myotonic dystrophy is discussed. Images Figure 1 Figure 2 Figure 3 Figure 4 PMID:6351629

  10. Myotonic dystrophy: genetic, clinical, and molecular analysis of patients from 41 Brazilian families.

    PubMed Central

    Passos-Bueno, M R; Cerqueira, A; Vainzof, M; Marie, S K; Zatz, M

    1995-01-01

    Results of genealogical, DNA, and clinical findings in 41 families with 235 patients affected with myotonic dystrophy (DM) led to the following observations. (1) The relative proportion of affected patients among blacks is apparently lower than among whites or orientals. (2) A significant excess of males was observed. (3) The frequency of DM patients who did not reproduce was similar for males and females; however, female patients had on average 25% fewer children than male patients. (4) There was a significant intergenerational increase in the mean length of the CTG repeat which was also correlated with the severity of the phenotype. (5) No significant difference was observed in the mean size of the CTG repeat in offspring of male as compared to female transmitters. (6) With the exception of the congenital cases of maternal origin, the largest expansions were paternally inherited, but did not lead to congenital DM. Images PMID:7897620

  11. Splicing biomarkers of disease severity in myotonic dystrophy

    PubMed Central

    Nakamori, Masayuki; Sobczak, Krzysztof; Puwanant, Araya; Welle, Steve; Eichinger, Katy; Pandya, Shree; Dekdebrun, Jeannne; Heatwole, Chad R.; McDermott, Michael P.; Chen, Tian; Cline, Melissa; Tawil, Rabi; Osborne, Robert J.; Wheeler, Thurman M.; Swanson, Maurice; Moxley, Richard T.; Thornton, Charles A.

    2014-01-01

    Objective To develop RNA splicing biomarkers of disease severity and therapeutic response in myotonic dystrophy type 1 (DM1) and type 2 (DM2). Methods In a discovery cohort we used microarrays to perform global analysis of alternative splicing in DM1 and DM2. The newly identified splicing changes were combined with previous data to create a panel of 50 putative splicing defects. In a validation cohort of 50 DM1 subjects we measured the strength of ankle dorsiflexion (ADF) and then obtained a needle biopsy of tibialis anterior (TA) to analyze splice events in muscle RNA. The specificity of DM-associated splicing defects was assessed in disease controls. The CTG expansion size in muscle tissue was determined by Southern blot. The reversibility of splicing defects was assessed in transgenic mice by using antisense oligonucleotides (ASOs) to reduce levels of toxic RNA. Results Forty-two splicing defects were confirmed in TA muscle in the validation cohort. Among these, 20 events showed graded changes that correlated with ADF weakness. Five other splice events were strongly affected in DM1 subjects with normal ADF strength. Comparison to disease controls and mouse models indicated that splicing changes were DM-specific, mainly attributable to MBNL1 sequestration, and reversible in mice by targeted knockdown of toxic RNA. Splicing defects and weakness were not correlated with CTG expansion size in muscle tissue. Interpretation Alternative splicing changes in skeletal muscle may serve as biomarkers of disease severity and therapeutic response in myotonic dystrophy. PMID:23929620

  12. Myotonic Dystrophy: Increased expression of the normal allele in CDM infants muscle

    SciTech Connect

    Radvanyi, H.H.; Gourdon, G.; Junien, C. |

    1994-09-01

    Myotonic dystrophy (DM) is an autosomal dominant multisystemic disorder characterized by a highly variable clinical phenotype. The mutation has been identified as an unstable trinucleotide CTG repeat in the 3{prime} untranslated region of the myotonin-protein kinase (MT-PK) gene. Congenital myotonic dystrophy (CDM), which represents the most severe phenotype, is exclusively maternally inherited. Recent studies, analysis by Northern blots and RT-PCR provided apparently conflicting results on the mutated allele expression in samples from congenitally affected children. The level of expression of the mutant allele depends on the extent of the repeat in the adult form and is no longer expressed when over 800-1300 repeats, whether in adult forms or in CDM. Could this decrease account for the late onset forms? However, the differences between the two phenotypes cannot be explained by the same mechanism. Alternatively, these differences could be due to differences in expression of the normal allele. We analyzed by quantitative RT-PCR the expression of the MT-PK gene in muscle samples from four CDM infants and two aged-matched normal controls. In two of these, the mutant allele (3.3 and 8 kb) was undetectable on Northern blots. We observed an increased expression of the MT-PK gene (10- to 20-fold) in tissues of severely affected congenital patients which can be attributed to the normal allele. Since expression of the normal allele is either normal or slightly decreased in the adult form, the dramatic increase in the congenital form could reflect a disturbance in muscle differentiation. Expression studies of MT-PK at different stages of development and, especially after the 20th week, are therefore required.

  13. Negative expansion of the myotonic dystrophy unstable sequence

    SciTech Connect

    Abeliovich, D.; Lerer, I.; Pashut-Lavon, I.; Shmueli, E. ); Raas-Rothschild, A.; Frydman, M. )

    1993-06-01

    The authors have analyzed the unstable fragment of the myotonic dystrophy (DM) gene in a pregnancy at 50% risk for DM. The affected father in this family had a 3.0-kb expansion of the DM unstable region. The fetus inherited the mutated gene, but with an expansion of 0.5 kb. This case represented a counseling problem in light of the absence of data concerning [open quotes]negative expansion[close quotes]. Analysis of the DM gene in 17 families with 72 affected individuals revealed four more cases of negative expansions, all of them in paternal transmissions. The possible significance of this finding is discussed. 21 refs., 3 figs., 3 tabs.

  14. Oropharyngeal dysphagia in myotonic dystrophy type 1: a systematic review.

    PubMed

    Pilz, Walmari; Baijens, Laura W J; Kremer, Bernd

    2014-06-01

    A systematic review was conducted to investigate the pathophysiology of and diagnostic procedures for oropharyngeal dysphagia in myotonic dystrophy (MD). The electronic databases Embase, PubMed, and The Cochrane Library were used. The search was limited to English, Dutch, French, German, Spanish, and Portuguese publications. Sixteen studies met the inclusion criteria. Two independent reviewers assessed the methodological quality of the included articles. Swallowing assessment tools, the corresponding protocols, the studies' outcome measurements, and main findings are summarized and presented. The body of literature on pathophysiology of swallowing in dysphagic patients with MD type 1 remains scant. The included studies are heterogeneous with respect to design and outcome measures and hence are not directly comparable. More importantly, most studies had methodological problems. These are discussed in detail and recommendations for further research on diagnostic examinations for swallowing disorders in patients with MD type 1 are provided.

  15. A case of myotonic dystrophy with electrolyte imbalance.

    PubMed

    Ko, Weon-Jin; Kim, Kwang-Yeol; Kim, So-Mi; Hong, Seung-Jae; Lee, Sang-Hoon; Song, Ran; Yang, Hyung-In; Lee, Yeon-Ah

    2013-07-01

    Type 1 myotonic dystrophy (DM1) is an autosomal-dominant inherited disorder with a multisystem involvement, caused by an abnormal expansion of the CTG sequence of the dystrophic myotonia protein kinase (DMPK) gene. DM1 is a variable multisystem disorder with muscular and nonmuscular abnormalities. Increasingly, endocrine abnormalities, such as gonadal, pancreatic, and adrenal dysfunction are being reported. But, Electrolytes imbalance is a very rare condition in patients with DM1 yet. Herein we present a 42-yr-old Korean male of DM1 with abnormally elevated serum sodium and potassium. The patient had minimum volume of maximally concentrated urine without water loss. It was only cured by normal saline hydration. The cause of hypernatremia was considered by primary hypodipsia. Hyperkalemic conditions such as renal failure, pseudohyperkalemia, cortisol deficiency and hyperkalemic periodic paralysis were excluded. Further endocrine evaluation suggested selective hyperreninemic hypoaldosteronism as a cause of hyperkalemia.

  16. Symptom Burden in Persons with Myotonic and Facioscapulohumeral Muscular Dystrophy

    PubMed Central

    Smith, Amanda E.; McMullen, Kara; Jensen, Mark P.; Carter, Gregory T.; Molton, Ivan R.

    2013-01-01

    Objective This study examines the prevalence of pain, fatigue, imbalance, memory impairment and vision loss in persons with myotonic and facioscapulohumeral dystrophy, and their association with functioning. Design A survey (n=170) included measures of severity (0–10 scales) and course of these symptoms, as well as measures of social integration, home competency, mental health and productive activity. Descriptive and regression analyses examined the associations between symptoms and functioning. Results Fatigue (91%), imbalance (82%) and pain (77%) were most commonly reported. The most severe symptom was fatigue (mean severity 5.14 ± 2.81), followed by imbalance (4.95 ± 3.25). Symptoms were most likely to stay the same or worsen since onset. Controlling for potential medical and demographic confounds, symptoms were associated with 17% of the mental health variance, 10% of home competency, 10% of social integration, 16% of productive activity for DM1 and 12% of productive activity for FSHD. Conclusions Pain, fatigue and imbalance are common in persons with muscular dystrophy. Interventions may be useful to mitigate their impact on functioning. Further research should examine these relationships to guide clinical practices. PMID:24247759

  17. Cardiac involvement in myotonic muscular dystrophy (Steinert's disease): a prospective study of 25 patients

    SciTech Connect

    Perloff, J.K.; Stevenson, W.G.; Roberts, N.K.; Cabeen, W.; Weiss, J.

    1984-11-01

    The presence, degree and frequency of disorders of cardiac conduction and rhythm and of regional or global myocardial dystrophy or myotonia have not previously been studied prospectively and systematically in the same population of patients with myotonic dystrophy. Accordingly, 25 adults with classic Steinert's disease underwent electrocardiography, 24-hour ambulatory electrocardiography, vectorcardiography, chest x-rays, echocardiography, electrophysiologic studies, and technetium-99m angiography. Clinically important cardiac manifestations of myotonic dystrophy reside in specialized tissues rather than in myocardium. Involvement is relatively specific, primarily assigned to the His-Purkinje system. The cardiac muscle disorder takes the form of dystrophy rather than myotonia, and is not selective, appearing with approximately equal distribution in all 4 chambers. Myocardial dystrophy seldom results in clinically overt ventricular failure, but may be responsible for atrial and ventricular arrhythmias. Since myotonic dystrophy is genetically transmitted, a primary biochemical defect has been proposed with complete expression of the gene toward striated muscle tissue, whether skeletal or cardiac. Specialized cardiac tissue and myocardium have close, if not identical, embryologic origins, so it is not surprising that the genetic marker affects both. Cardiac involvement is therefore an integral part of myotonic dystrophy, targeting particularly the infranodal conduction system, to a lesser extent the sinus node, and still less specifically, the myocardium.

  18. Myotonia and flaccid dysarthria in patients with adult onset myotonic dystrophy

    PubMed Central

    de Swart, B J M; van Engelen, B G M; van de Kerkhof, J P B M; Maassen, B

    2004-01-01

    Objective: To specify and quantify possible defects in speech execution in patients with adult onset myotonic dystrophy. Methods: Studies on speech production were done on 30 mildly affected patients with myotonic dystrophy. Special attention was paid to myotonia. Because muscle activity can result in a decrease of myotonia, speech characteristics were measured before and after warm up. The possibility that warming up causes increased weakness was also assessed. Results: As with other motor skills, a warm up effect was found in speech production, resulting in an increase in repetition rate and a decrease in variability of repetition rate. Signs of fatigue did not occur. Conclusions: Warming up is valuable for patients with myotonic dystrophy in reducing the influence of myotonia on speech production. PMID:15377703

  19. Evidence for meiotic drive at the myotonic dystrophy locus

    SciTech Connect

    Shaw, A.M.; Barnetson, R.A.; Phillips, M.F.

    1994-09-01

    Myotonic dystrophy (DM), an autosomal dominant disorder, is the most common form of adult muscular dystrophy, affecting at least 1 in 8000 of the population. It is a multisystemic disorder, primarily characterized by myotonia, muscle wasting and cataract. The molecular basis of DM is an expanded CTG repeat located within the 3{prime} untranslated region of a putative serine-threonine protein kinase on chromosome 19q13.3. DM exhibits anticipation, that is, with successive generations there is increasing disease severity and earlier age of onset. This mechanism and the fact that the origin of the disease has been attributed to one or a small number of founder chromosomes suggests that, in time, DM should die out. Meiotic drive has been described as a way in which certain alleles are transmitted to succeeding generations in preference to others: preferential transmission of large CTG alleles may account for their continued existence in the gene pool. There is evidence that a CTG allele with > 19 repeats may gradually increase in repeat number over many generations until it is sufficiently large to give a DM phenotype. We report a study of 495 transmissions from individuals heterozygous for the CTG repeat and with repeat numbers within the normal range (5-30). Alleles were simply classified as large or small relative to the other allele in an individual. Of 242 male meioses, 126 transmissions from parent to child were of the larger allele to their offspring (57.7%, p=0.014). This shows that there is strong evidence for meiotic drive favoring the transmission of the larger DM allele in unaffected individuals. Contrary to a previous report of meiotic drive in the male, we have shown that females preferentially transmit the larger DM allele. Taken together, the data suggest the occurrence of meiotic drive in both males and females in this locus.

  20. In vitro mapping of Myotonic Dystrophy (DM) gene promoter

    SciTech Connect

    Storbeck, C.J.; Sabourin, L.; Baird, S.

    1994-09-01

    The Myotonic Dystrophy Kinase (DMK) gene has been cloned and shared homology to serine/threonine protein kinases. Overexpression of this gene in stably transfected mouse myoblasts has been shown to inhibit fusion into myotubes while myoblasts stably transfected with an antisense construct show increased fusion potential. These experiments, along with data showing that the DM gene is highly expressed in muscle have highlighted the possibility of DMK being involved in myogenesis. The promoter region of the DM gene lacks a consensus TATA box and CAAT box, but harbours numerous transcription binding sites. Clones containing extended 5{prime} upstream sequences (UPS) of DMK only weakly drive the reporter gene chloramphenicol acetyl transferase (CAT) when transfected into C2C12 mouse myoblasts. However, four E-boxes are present in the first intron of the DM gene and transient assays show increased expression of the CAT gene when the first intron is present downstream of these 5{prime} UPS in an orientation dependent manner. Comparison between mouse and human sequence reveals that the regions in the first intron where the E-boxes are located are highly conserved. The mapping of the promoter and the importance of the first intron in the control of DMK expression will be presented.

  1. [Social Cognitive Impairment in Myotonic Dystrophy Type 1].

    PubMed

    Kobayakawa, Mutsutaka

    2016-02-01

    Myotonic dystrophy type 1 (DM 1) is a heritable, multisystem disease that affects not only the muscles but also the brain. DM 1 is often accompanied by developmental behavioral disorders, such as autism spectrum disorders. The autistic traits in DM 1 may be related to social cognitive dysfunction. The social cognitive function of patients with DM 1 was examined with respect to facial emotion recognition and theory of mind, which is the specific cognitive ability to understand the mental states of other people. With respect to facial emotion recognition, the sensitivities to disgust and anger were lower among patients with DM 1 than among healthy subjects, and this difference could not be attributed to visual impairment. To examine the theory of mind ability, the "Reading the Mind in the Eyes" test and the faux pas recognition test were used. Patients with DM 1 were found to be impaired in both tests, but the results were not attributed to visual ability and lexical comprehension. The possible causes of social cognitive dysfunction in DM 1 are the l cerebral atrophy and white matter abnormalities in the temporal, frontal, and insular cortex. Dysfunctions in these areas may affect the emotional and theory of mind abilities in DM 1, which result in the behavioral and communication disorders.

  2. Myotonic Dystrophy-1 Complicated by Factor-V (Leiden) Mutation

    PubMed Central

    Finsterer, Josef; Stöllberger, Claudia

    2015-01-01

    Objectives. Presence of a factor-V Leiden mutation in a patient with myotonic dystrophy type 1 (DM1) has been reported only once. Here we report the second DM1 patient carrying a factor-V mutation who died from long-term complications of this mutation. Case Report. A 66-year-old DM1 patient with multi-organ-disorder syndrome developed a first deep venous thrombosis (DVT) and consecutive pulmonary embolism (PE) at age 50 y. Acetyl-salicylic acid was given. One year later he experienced a second DVT; that is why phenprocoumon was started. Despite anticoagulation, he experienced a third DVT bilaterally and a second PE bilaterally at 61 y; that is why a vena cava filter was additionally deployed. Despite therapeutic anticoagulation, he experienced a vena cava filter thrombosis at age 62 y. Genetic workup revealed a heterozygous factor-V mutation in addition to a CTG-repeat expansion of 500. As a consequence of PE he developed chronic obstructive pulmonary disease and experienced recurrent pulmonary infections, which were lastly responsible for decease at age 66 y despite intensive care measures. Conclusion. The heterozygous Leiden mutation may severely affect DM1 patients to such a degree that they die from its complications. If DM1 patients present with unusual manifestations, search for causes other than a CTG-repeat expansion is indicated. PMID:25918532

  3. Synaptic protein dysregulation in myotonic dystrophy type 1

    PubMed Central

    Hernández-Hernández, Oscar; Sicot, Géraldine; Dinca, Diana M.; Huguet, Aline; Nicole, Annie; Buée, Luc; Munnich, Arnold; Sergeant, Nicolas; Gourdon, Geneviève; Gomes-Pereira, Mário

    2013-01-01

    The toxicity of expanded transcripts in myotonic dystrophy type 1 (DM1) is mainly mediated by the disruption of alternative splicing. However, the detailed disease mechanisms in the central nervous system (CNS) have not been fully elucidated. In our recent study, we demonstrated that the accumulation of mutant transcripts in the CNS of a mouse model of DM1 disturbs splicing in a region-specific manner. We now discuss that the spatial- and temporal-regulated expression of splicing factors may contribute to the region-specific spliceopathy in DM1 brains. In the search for disease mechanisms operating in the CNS, we found that the expression of expanded CUG-containing RNA affects the expression and phosphorylation of synaptic vesicle proteins, possibly contributing to DM1 neurological phenotypes. Although mediated by splicing regulators with a described role in DM1, the misregulation of synaptic proteins was not associated with missplicing of their coding transcripts, supporting the view that DM1 mechanisms in the CNS have also far-reaching implications beyond the disruption of a splicing program. PMID:25003003

  4. Anesthetic and surgical complications in 219 cases of myotonic dystrophy.

    PubMed

    Mathieu, J; Allard, P; Gobeil, G; Girard, M; De Braekeleer, M; Bégin, P

    1997-12-01

    The objective of this study was to assess the frequency, type, and severity of perioperative complications after a first surgery under general anesthesia in patients with myotonic dystrophy (DM) and to measure the association with suspected risk factors. Numerous cases of perioperative complications in DM patients have been reported. Hazards have been associated with the use of thiopentone, suxamethonium, neostigmine, and halothane. A retrospective study of perioperative complications was conducted for 219 DM patients who had their first surgery under general anesthesia at the Chicoutimi Hospital. The overall frequency of complications was 8.2% (18 of 219). Most complications (16 of 18) were pulmonary, including five patients with acute ventilatory failure necessitating ventilatory support, four patients with atelectasis, and three patients with pneumonia. Using multivariate analysis, we found that the risk of perioperative pulmonary complications (PPC) was significantly higher after an upper abdominal surgery (odds ratio (OR), 24.4; 95% CI, 4.0 to 149.3) and for patients with a severe muscular disability, as assessed by the presence of proximal limb weakness (OR, 14.1; 95% CI, 1.5 to 134.4). The likelihood of PPC was not related to any specific anesthetic drug. Because of the increased risk of PPC, careful monitoring during the early postoperative period, protection of upper airways, chest physiotherapy, and incentive spirometry are mandatory in all symptomatic DM patients, particularly those with a severe muscular disability or those who have undergone an upper abdominal surgery.

  5. Compound loss of muscleblind-like function in myotonic dystrophy

    PubMed Central

    Lee, Kuang-Yung; Li, Moyi; Manchanda, Mini; Batra, Ranjan; Charizanis, Konstantinos; Mohan, Apoorva; Warren, Sonisha A; Chamberlain, Christopher M; Finn, Dustin; Hong, Hannah; Ashraf, Hassan; Kasahara, Hideko; Ranum, Laura P W; Swanson, Maurice S

    2013-01-01

    Myotonic dystrophy (DM) is a multi-systemic disease that impacts cardiac and skeletal muscle as well as the central nervous system (CNS). DM is unusual because it is an RNA-mediated disorder due to the expression of toxic microsatellite expansion RNAs that alter the activities of RNA processing factors, including the muscleblind-like (MBNL) proteins. While these mutant RNAs inhibit MBNL1 splicing activity in heart and skeletal muscles, Mbnl1 knockout mice fail to recapitulate the full-range of DM symptoms in these tissues. Here, we generate mouse Mbnl compound knockouts to test the hypothesis that Mbnl2 functionally compensates for Mbnl1 loss. Although Mbnl1−/−; Mbnl2−/− double knockouts (DKOs) are embryonic lethal, Mbnl1−/−; Mbnl2+/− mice are viable but develop cardinal features of DM muscle disease including reduced lifespan, heart conduction block, severe myotonia and progressive skeletal muscle weakness. Mbnl2 protein levels are elevated in Mbnl1−/− knockouts where Mbnl2 targets Mbnl1-regulated exons. These findings support the hypothesis that compound loss of MBNL function is a critical event in DM pathogenesis and provide novel mouse models to investigate additional pathways disrupted in this RNA-mediated disease. PMID:24293317

  6. Two Cases of Endometrial Cancer in Twin Sisters with Myotonic Dystrophy

    PubMed Central

    2016-01-01

    We describe two cases of endometrial cancer (EC) occurring in nulligravid twin sisters with myotonic dystrophy. Both tested negative for Lynch syndrome and both were treated with laparoscopic hysterectomy with bilateral salpingooophorectomy and adjuvant radiotherapy. Although EC tends to run in families, the diagnosis in itself is not considered sufficient cause for screening or prophylactic measures in close relatives. However, the presence of additional risk factors, such as nulligravidity and myotonic dystrophy in the underlying cases, may call for extra vigilance in first-degree family members. PMID:27595026

  7. Development of a genomic DNA reference material panel for myotonic dystrophy type 1 (DM1) genetic testing.

    PubMed

    Kalman, Lisa; Tarleton, Jack; Hitch, Monica; Hegde, Madhuri; Hjelm, Nick; Berry-Kravis, Elizabeth; Zhou, Lili; Hilbert, James E; Luebbe, Elizabeth A; Moxley, Richard T; Toji, Lorraine

    2013-07-01

    Myotonic dystrophy type 1 (DM1) is caused by expansion of a CTG triplet repeat in the 3' untranslated region of the DMPK gene that encodes a serine-threonine kinase. Patients with larger repeats tend to have a more severe phenotype. Clinical laboratories require reference and quality control materials for DM1 diagnostic and carrier genetic testing. Well-characterized reference materials are not available. To address this need, the Centers for Disease Control and Prevention-based Genetic Testing Reference Material Coordination Program, in collaboration with members of the genetic testing community, the National Registry of Myotonic Dystrophy and Facioscapulohumeral Muscular Dystrophy Patients and Family Members, and the Coriell Cell Repositories, has established and characterized cell lines from patients with DM1 to create a reference material panel. The CTG repeats in genomic DNA samples from 10 DM1 cell lines were characterized in three clinical genetic testing laboratories using PCR and Southern blot analysis. DMPK alleles in the samples cover four of five DM1 clinical categories: normal (5 to 34 repeats), mild (50 to 100 repeats), classical (101 to 1000 repeats), and congenital (>1000 repeats). We did not identify or establish Coriell cell lines in the premutation range (35 to 49 repeats). These samples are publicly available for quality control, proficiency testing, test development, and research and should help improve the accuracy of DM1 testing. PMID:23680132

  8. Muscle wasting in myotonic dystrophies: a model of premature aging

    PubMed Central

    Mateos-Aierdi, Alba Judith; Goicoechea, Maria; Aiastui, Ana; Fernández-Torrón, Roberto; Garcia-Puga, Mikel; Matheu, Ander; López de Munain, Adolfo

    2015-01-01

    Myotonic dystrophy type 1 (DM1 or Steinert’s disease) and type 2 (DM2) are multisystem disorders of genetic origin. Progressive muscular weakness, atrophy and myotonia are the most prominent neuromuscular features of these diseases, while other clinical manifestations such as cardiomyopathy, insulin resistance and cataracts are also common. From a clinical perspective, most DM symptoms are interpreted as a result of an accelerated aging (cataracts, muscular weakness and atrophy, cognitive decline, metabolic dysfunction, etc.), including an increased risk of developing tumors. From this point of view, DM1 could be described as a progeroid syndrome since a notable age-dependent dysfunction of all systems occurs. The underlying molecular disorder in DM1 consists of the existence of a pathological (CTG) triplet expansion in the 3′ untranslated region (UTR) of the Dystrophia Myotonica Protein Kinase (DMPK) gene, whereas (CCTG)n repeats in the first intron of the Cellular Nucleic acid Binding Protein/Zinc Finger Protein 9 (CNBP/ZNF9) gene cause DM2. The expansions are transcribed into (CUG)n and (CCUG)n-containing RNA, respectively, which form secondary structures and sequester RNA-binding proteins, such as the splicing factor muscleblind-like protein (MBNL), forming nuclear aggregates known as foci. Other splicing factors, such as CUGBP, are also disrupted, leading to a spliceopathy of a large number of downstream genes linked to the clinical features of these diseases. Skeletal muscle regeneration relies on muscle progenitor cells, known as satellite cells, which are activated after muscle damage, and which proliferate and differentiate to muscle cells, thus regenerating the damaged tissue. Satellite cell dysfunction seems to be a common feature of both age-dependent muscle degeneration (sarcopenia) and muscle wasting in DM and other muscle degenerative diseases. This review aims to describe the cellular, molecular and macrostructural processes involved in the

  9. Two cases of myotonic dystrophy manifesting various ophthalmic findings with genetic evaluation.

    PubMed

    Kang, Min Ji; Yim, Hye Bin; Hwang, Hyung Bin

    2016-07-01

    We report two cases of myotonic dystrophy in one family; both diagnosed from genetic analysis following ophthalmic indications, but before the manifestation of systemic symptoms. A 39-year-old female visited our clinic for routine examination. Mild ptosis, sluggish pupillary response, and bilateral snowflake cataracts were found. Fundus examination revealed an increased cup-to-disc ratio (CDR) in both eyes and a defect in the retinal nerve fiber layer in the right eye. Intraocular pressure was low, but within the normal range in both eyes. Because cataracts are characteristic of myotonic dystrophy, we suggested that her 14-year-old daughter, who did not have any systemic complaints, undergo ophthalmic examination. She also had mild ptosis and snowflake cataracts. Both patients underwent genetic evaluation and were diagnosed with myotonic dystrophy caused by unstable expansion of cytosine-thymine-guanine trinucleotide repeats in the dystrophia myotonica-protein kinase gene. Ophthalmologists can diagnose myotonic dystrophy based on clinical and genetic findings, before the manifestation of systemic abnormalities. PMID:27609169

  10. Two cases of myotonic dystrophy manifesting various ophthalmic findings with genetic evaluation

    PubMed Central

    Kang, Min Ji; Yim, Hye Bin; Hwang, Hyung Bin

    2016-01-01

    We report two cases of myotonic dystrophy in one family; both diagnosed from genetic analysis following ophthalmic indications, but before the manifestation of systemic symptoms. A 39-year-old female visited our clinic for routine examination. Mild ptosis, sluggish pupillary response, and bilateral snowflake cataracts were found. Fundus examination revealed an increased cup-to-disc ratio (CDR) in both eyes and a defect in the retinal nerve fiber layer in the right eye. Intraocular pressure was low, but within the normal range in both eyes. Because cataracts are characteristic of myotonic dystrophy, we suggested that her 14-year-old daughter, who did not have any systemic complaints, undergo ophthalmic examination. She also had mild ptosis and snowflake cataracts. Both patients underwent genetic evaluation and were diagnosed with myotonic dystrophy caused by unstable expansion of cytosine-thymine-guanine trinucleotide repeats in the dystrophia myotonica-protein kinase gene. Ophthalmologists can diagnose myotonic dystrophy based on clinical and genetic findings, before the manifestation of systemic abnormalities. PMID:27609169

  11. Myotonic dystrophy CTG expansion affects synaptic vesicle proteins, neurotransmission and mouse behaviour.

    PubMed

    Hernández-Hernández, Oscar; Guiraud-Dogan, Céline; Sicot, Géraldine; Huguet, Aline; Luilier, Sabrina; Steidl, Esther; Saenger, Stefanie; Marciniak, Elodie; Obriot, Hélène; Chevarin, Caroline; Nicole, Annie; Revillod, Lucile; Charizanis, Konstantinos; Lee, Kuang-Yung; Suzuki, Yasuhiro; Kimura, Takashi; Matsuura, Tohru; Cisneros, Bulmaro; Swanson, Maurice S; Trovero, Fabrice; Buisson, Bruno; Bizot, Jean-Charles; Hamon, Michel; Humez, Sandrine; Bassez, Guillaume; Metzger, Friedrich; Buée, Luc; Munnich, Arnold; Sergeant, Nicolas; Gourdon, Geneviève; Gomes-Pereira, Mário

    2013-03-01

    Myotonic dystrophy type 1 is a complex multisystemic inherited disorder, which displays multiple debilitating neurological manifestations. Despite recent progress in the understanding of the molecular pathogenesis of myotonic dystrophy type 1 in skeletal muscle and heart, the pathways affected in the central nervous system are largely unknown. To address this question, we studied the only transgenic mouse line expressing CTG trinucleotide repeats in the central nervous system. These mice recreate molecular features of RNA toxicity, such as RNA foci accumulation and missplicing. They exhibit relevant behavioural and cognitive phenotypes, deficits in short-term synaptic plasticity, as well as changes in neurochemical levels. In the search for disease intermediates affected by disease mutation, a global proteomics approach revealed RAB3A upregulation and synapsin I hyperphosphorylation in the central nervous system of transgenic mice, transfected cells and post-mortem brains of patients with myotonic dystrophy type 1. These protein defects were associated with electrophysiological and behavioural deficits in mice and altered spontaneous neurosecretion in cell culture. Taking advantage of a relevant transgenic mouse of a complex human disease, we found a novel connection between physiological phenotypes and synaptic protein dysregulation, indicative of synaptic dysfunction in myotonic dystrophy type 1 brain pathology.

  12. Myotonic dystrophy CTG expansion affects synaptic vesicle proteins, neurotransmission and mouse behaviour

    PubMed Central

    Hernández-Hernández, Oscar; Guiraud-Dogan, Céline; Sicot, Géraldine; Huguet, Aline; Luilier, Sabrina; Steidl, Esther; Saenger, Stefanie; Marciniak, Elodie; Obriot, Hélène; Chevarin, Caroline; Nicole, Annie; Revillod, Lucile; Charizanis, Konstantinos; Lee, Kuang-Yung; Suzuki, Yasuhiro; Kimura, Takashi; Matsuura, Tohru; Cisneros, Bulmaro; Swanson, Maurice S.; Trovero, Fabrice; Buisson, Bruno; Bizot, Jean-Charles; Hamon, Michel; Humez, Sandrine; Bassez, Guillaume; Metzger, Friedrich; Buée, Luc; Munnich, Arnold; Sergeant, Nicolas; Gourdon, Geneviève

    2013-01-01

    Myotonic dystrophy type 1 is a complex multisystemic inherited disorder, which displays multiple debilitating neurological manifestations. Despite recent progress in the understanding of the molecular pathogenesis of myotonic dystrophy type 1 in skeletal muscle and heart, the pathways affected in the central nervous system are largely unknown. To address this question, we studied the only transgenic mouse line expressing CTG trinucleotide repeats in the central nervous system. These mice recreate molecular features of RNA toxicity, such as RNA foci accumulation and missplicing. They exhibit relevant behavioural and cognitive phenotypes, deficits in short-term synaptic plasticity, as well as changes in neurochemical levels. In the search for disease intermediates affected by disease mutation, a global proteomics approach revealed RAB3A upregulation and synapsin I hyperphosphorylation in the central nervous system of transgenic mice, transfected cells and post-mortem brains of patients with myotonic dystrophy type 1. These protein defects were associated with electrophysiological and behavioural deficits in mice and altered spontaneous neurosecretion in cell culture. Taking advantage of a relevant transgenic mouse of a complex human disease, we found a novel connection between physiological phenotypes and synaptic protein dysregulation, indicative of synaptic dysfunction in myotonic dystrophy type 1 brain pathology. PMID:23404338

  13. Modeling Myotonic Dystrophy 1 in C2C12 Myoblast Cells.

    PubMed

    Liang, Rui; Dong, Wei; Shen, Xiaopeng; Peng, Xiaoping; Aceves, Angie G; Liu, Yu

    2016-01-01

    Myotonic dystrophy 1 (DM1) is a common form of muscular dystrophy. Although several animal models have been established for DM1, myoblast cell models are still important because they offer an efficient cellular alternative for studying cellular and molecular events. Though C2C12 myoblast cells have been widely used to study myogenesis, resistance to gene transfection, or viral transduction, hinders research in C2C12 cells. Here, we describe an optimized protocol that includes daily maintenance, transfection and transduction procedures to introduce genes into C2C12 myoblasts and the induction of myocyte differentiation. Collectively, these procedures enable best transfection/transduction efficiencies, as well as consistent differentiation outcomes. The protocol described in establishing DM1 myoblast cell models would benefit the study of myotonic dystrophy, as well as other muscular diseases. PMID:27501221

  14. Cancer Risk among Patients with Myotonic Muscular Dystrophy

    PubMed Central

    Gadalla, Shahinaz M; Lund, Marie; Pfeiffer, Ruth M; Gørtz, Sanne; Mueller, Christine M; Moxley, Richard T; Kristinsson, Sigurdur Y; Björkholm, Magnus; Shebl, Fatma M; Hilbert, James E; Landgren, Ola; Wohlfahrt, Jan; Melbye, Mads; Greene, Mark H

    2012-01-01

    Context Myotonic muscular dystrophy (MMD) is an autosomal dominant multisystem neuromuscular disorder characterized by unstable nucleotide repeat expansions. Case reports have suggested that MMD patients may be at increased risk of malignancy, putative risks which have never been quantified. Objective To quantitatively evaluate cancer risk in patients with MMD, overall, and by sex and age. Design, Setting, and Participants We identified 1,658 patients with an MMD discharge diagnosis in the Swedish Inpatient Hospital or Danish Patient Discharge Registries between 1977 and 2008. We linked these patients to their corresponding cancer registry. Patients were followed from date of first MMD-related inpatient or outpatient contact, to first cancer diagnosis, death, emigration, or completion of cancer registration. Main Outcome Measures Risks of all cancers combined, and by anatomic site, stratified by sex and age. Results 104 patients with an inpatient or outpatient discharge diagnosis of MMD developed cancer during post-discharge follow-up. This corresponds to an observed cancer rate of 73.4/10,000 person-years in MMD versus an expected rate of 36.9/10,000 in the general Swedish and Danish populations combined (SIR =2.0, 95% CI =1.6–2.4). Specifically, we observed significant excess risks of cancers of the endometrium (observed rate=16.1/10,000 person-years: SIR=7.6, 95%CI=4.0–13.2), brain (observed rate=4.9/10,000 person-years: SIR=5.3, 95%CI=2.3–10.4), ovary (observed rate=10.3/10,000 person-years: SIR=5.2, 95% CI=2.3–10.2), and colon (observed rate=7.1/10,000 person-years: SIR=2.9, 95%CI=1.5–5.1). Cancer risks were similar in females and males after excluding genital organ tumors (SIR=1.9, 95% CI=1.4–2.5 vs. 1.8, 95% CI=1.3–2.5, respectively, p-heterogeneity=0.81; observed rates=64.5 and 47.7/10,000 person-years in women and men, respectively), The same pattern of cancer excess was observed first in the Swedish, and then in the Danish cohorts, which

  15. Does quantitative EMG differ myotonic dystrophy type 2 and type 1?

    PubMed

    Szmidt-Salkowska, Elzbieta; Gawel, Malgorzata; Lusakowska, Anna; Nojszewska, Monika; Lipowska, Marta; Sulek, Anna; Krysa, Wioletta; Rajkiewicz, Marta; Seroka, Andrzej; Kaminska, Anna M

    2014-10-01

    Genetic testing is considered the only reliable diagnostic approach in myotonic dystrophy. However it has recently been reported that a considerable number of patients with genetically proven types of the disease have unusual phenotypic presentation. The aim of our study was to evaluate motor unit reorganization reflected by various electrophysiological abnormalities in myotonic dystrophies and to compare findings between type 1 (DM 1) and type 2 myotonic dystrophy (DM2). Quantitative electromyography (EMG) recordings in 63 patients (33 with DM1 and 30 with DM2) from the biceps brachii (BB), rectus femoris (RF), first dorsal interosseus (FDI), and tibialis anterior (TA) muscles were analyzed. Mean amplitude and size index (SI) of motor unit potentials recorded in TA and RF muscles, mean potential duration in TA, and mean SI and the number of outliers with amplitude above the normal range in BB were significantly increased in DM2 as compared to DM1. Myotonic discharges were recorded more frequently in DM1 than in DM2. EMG findings significantly differ between DM1 and DM2. The presence of high amplitude potentials in lower limb muscles in DM2 patients, atypical for myogenic muscle lesions, could be explained by muscle fiber hypertrophy observed in muscle biopsies.

  16. Experienced fatigue in facioscapulohumeral dystrophy, myotonic dystrophy, and HMSN-I

    PubMed Central

    Kalkman, J; Schillings, M; van der Werf, S P; Padberg, G; Zwarts, M; van Engelen, B G M; Bleijenberg, G

    2005-01-01

    Objective: To assess the prevalence of severe fatigue and its relation to functional impairment in daily life in patients with relatively common types of neuromuscular disorders. Methods: 598 patients with a neuromuscular disease were studied (139 with facioscapulohumeral dystrophy, 322 with adult onset myotonic dystrophy, and 137 with hereditary motor and sensory neuropathy type I). Fatigue severity was assessed with Checklist Individual Strength (CIS-fatigue). Functional impairments in daily life were measured with the short form 36 item health questionnaire (SF-36). Results: The three different neuromuscular patient groups were of similar age and sex. Severe experienced fatigue was reported by 61–74% of the patients. Severely fatigued patients had more problems with physical functioning, social functioning, mental health, bodily pain, and general health perception. There were some differences between the three disorders in the effects of fatigue. Conclusions: Severe fatigue is reported by the majority of patients with relatively common types of neuromuscular disorders. Because experienced fatigue severity is associated with the severity of various functional impairments in daily life, it is a clinically and socially relevant problem in this group of patients. PMID:16170086

  17. The effects of myotonic dystrophy and Duchenne muscular dystrophy on the orofacial muscles and dentofacial morphology.

    PubMed

    Kiliaridis, S; Katsaros, C

    1998-12-01

    This article takes a closer view of two of the less rare myopathies, myotonic dystrophy (MyD) and Duchenne muscular dystrophy (DMD). A high prevalence of malocclusions was found among the patients affected by these diseases. The development of the malocclusions in MyD patients seems to be strongly related to the vertical aberration of their craniofacial growth due to the involvement of the masticator, muscles in association with the possibly less affected suprahyoid musculature. Thus, a new situation is established around the teeth transversely. The lowered tongue is not in a position to counterbalance the forces developed during the lowering of the mandible by the stretched facial musculature. This may affect the teeth transversely, decreasing the width of the palate and causing posterior crossbite. The lowered position of the mandible, in combination with the decreased biting forces, may permit an overeruption of the posterior teeth, with increased palatal vault height and development of anterior open bite. The development of the malocclusions in DMD patients also seems to be strongly related to the involvement of the orofacial muscles by the disease. However, the posterior crossbite is not developed owing to the narrow maxillary arch, as is the case in MyD patients. On the contrary, the posterior crossbite in DMD is due to the transversal expansion of the mandibular arch, possibly because of the decreased tonus of the masseter muscle near the molars, in combination with the enlarged hypotonic tongue and the predominance of the less affected orbicularis oris muscle.

  18. The myotonic dystrophy kinase 3{prime}-untranslated region and its effect on gene expression

    SciTech Connect

    Ang, C.W.Y.; Sabourin, L.A.; Narang, M.A.

    1994-09-01

    Myotonic dystrophy (DM) is an autosomal dominant neuromuscular disease involving the expansion of an unstable CTG repeat in the 3{prime}-untranslated (3{prime}-UTR) region of the DM kinase (DMK) gene. Increased levels of mRNA in congenital compared to normal tissue have been shown, suggesting elevated DMK levels may be responsible for the disease phenotype. To study the effect of the DMK 3{prime}UTR on gene expression, a reporter gene system was constructed using the constitutive CMV promoter with the chloramphenicol acetyl transferase (CAT) open reading frame and the DMK 3{prime}UTR containing from 5 repeats up to 90 repeats. Transient transfection into a rhabdomyosarcoma cell line shows a three-fold increase in CAT activity from constructs containing a wildtype 3{prime}UTR (5 and 20 repeats) compared to a control construct containing only a poly(A) signal. Reporter constructs with repeats in the protomutation (50 repeats) and mutation (90 repeats) range show a greater than 10-fold increase over control CAT activity. These results suggest the presence of elements in the DMK 3{prime}UTR capable of conferring increased gene expression. We are currently investigating cell-specific activity of the constructs and conducting deletion mapping to identify regulatory elements in the 3{prime}-UTR.

  19. Genetics Home Reference: Fukuyama congenital muscular dystrophy

    MedlinePlus

    ... and walking. Fukuyama congenital muscular dystrophy also impairs brain development. People with this condition have a brain abnormality ... cobblestones). These changes in the structure of the brain lead to significantly delayed development of speech and motor skills and moderate to ...

  20. Peripheral nerve conduction and central motor conduction after magnetic stimulation of the brain in myotonic dystrophy.

    PubMed

    Cruz Martínez, A

    1992-06-01

    Central motor conduction time was calculated after magnetic stimulation of the brain in 15 patients with myotonic dystrophy and in 38 healthy voluntaries of the same age. Conventional electromyography and motor and sensory conduction velocities were also performed. Central motor conduction time from vertex to C8 was within the normal range in all patients whereas motor conduction velocity of the peripheral nerve and amplitude of the nerve evoked potentials were slightly reduced in 3 and 2 cases respectively, supporting peripheral nerve involvement in some subjects. Our results suggest that the reported central nervous system involvement in myotonic dystrophy, including the nonspecific white matter lesions showed by magnetic resonance imaging, would not affect the conduction of the corticospinal tracts. Magnetic stimulation on the motor cortex is a painless method to study the central nervous system and apports a satisfactory approximation to central motor pathways conduction.

  1. Rac-1 and Raf-1 kinases, components of distinct signaling pathways, activate myotonic dystrophy protein kinase

    NASA Technical Reports Server (NTRS)

    Shimizu, M.; Wang, W.; Walch, E. T.; Dunne, P. W.; Epstein, H. F.

    2000-01-01

    Myotonic dystrophy protein kinase (DMPK) is a serine-threonine protein kinase encoded by the myotonic dystrophy (DM) locus on human chromosome 19q13.3. It is a close relative of other kinases that interact with members of the Rho family of small GTPases. We show here that the actin cytoskeleton-linked GTPase Rac-1 binds to DMPK, and coexpression of Rac-1 and DMPK activates its transphosphorylation activity in a GTP-sensitive manner. DMPK can also bind Raf-1 kinase, the Ras-activated molecule of the MAP kinase pathway. Purified Raf-1 kinase phosphorylates and activates DMPK. The interaction of DMPK with these distinct signals suggests that it may play a role as a nexus for cross-talk between their respective pathways and may partially explain the remarkable pleiotropy of DM.

  2. A comprehensive genetic diagnosis of Chinese muscular dystrophy and congenital myopathy patients by targeted next-generation sequencing.

    PubMed

    Dai, Yi; Wei, Xiaoming; Zhao, Yanhuan; Ren, Haitao; Lan, Zhangzhang; Yang, Yun; Chen, Lin; Cui, Liying

    2015-08-01

    Muscular dystrophies and congenital myopathies are a large group of heterogeneous inherited muscle disorders. The spectrum of muscular dystrophies and congenital myopathies extends to more than 50 diseases today, even excluding the common forms Duchenne Muscular Dystrophy, Myotonic Dystrophy and Facioscapulohumeral Dystrophy. Unfortunately, even by critical clinical evaluation and muscle pathology, diagnosis is still difficult. To potentially remediate this difficulty, we applied a microarray-based targeted next-generation sequencing (NGS) technology to diagnose these patients. There were 55 consecutive unrelated patients who underwent the test, 36 of which (65%) were found to have a causative mutation. Our result shows the accuracy and efficiency of next-generation sequencing in clinical circumstances and reflects the features and relative distribution of inherited myopathies in the Chinese population.

  3. [Congenital muscular dystrophies in children].

    PubMed

    Scavone-Mauro, Cristina; Barros, Graciela

    2013-09-01

    From the clinical and genetic point of view, congenital muscular dystrophies (CMD) are a heterogenic group of diseases within neuromuscular pathologies. The best known forms are: merosin deficiency CMD, collagen VI deficiency CMD, LMNA-related CMD, selenoprotein-related CMD (SEPN1) and alpha-dystroglycan-related CMD. They present with a broad spectrum of clinical phenotypes. Most of them are transmitted by recessive autosomal inheritance. The initial manifestations very often begin in infancy or in the neonatal period. There are clinical suspicions of the existence of hypotonia and paresis, and they are characterised by a dystrophic pattern in the muscular biopsy (muscle replaced by fibroadipose tissue, with necrosis and cell regeneration). Advances in the understanding of the molecular pathogenesis of CMD have made it possible to make further progress in the classification of the different subtypes. The aim of this review is to comment on the advances made in recent years as regards the classification of CMD in terms of genetics, the proteins involved and their clinical presentation.

  4. Computer method for the analysis of evoked motor unit potentials. 2. Duchenne, limb-girdle, facioscapulohumeral and myotonic muscular dystrophies.

    PubMed Central

    Ballantyne, J P; Hansen, S

    1975-01-01

    Single motor unit potentials recorded from surface electrodes over the extensor digitorum brevis muscle and evoked by stimulation of the anterior tibial nerve at the ankle were obtained by a computer subtraction method. Their latencies, durations, amplitudes, and areas were measured in control subjects and patients with Duchenne, limb-girdle, facioscapulohumeral, and myotonic muscular dystrophy. Lateral popliteal motor nerve conduction velocities were also recorded. In the muscular dystrophies there was a significant increase in both the latencies and durations of motor unit potentials, the latter in notable contrast with the findings of conventional needle electromyography. Fastest motor conduction velocities were significantly reduced in the limb-girdle, facioscapulohumeral, and myotonic muscular dystrophy patients, while the shortest distal motor latencies were significantly prolonged in these patients and those with Duchenne muscular dystrophy. The results support the presence of a definitive neurogenic influence in the muscular dystrophies. PMID:1151411

  5. A journey in bioinspired supramolecular chemistry: from molecular tweezers to small molecules that target myotonic dystrophy

    PubMed Central

    2016-01-01

    Summary This review summarizes part of the author’s research in the area of supramolecular chemistry, beginning with his early life influences and early career efforts in molecular recognition, especially molecular tweezers. Although designed to complex DNA, these hosts proved more applicable to the field of host–guest chemistry. This early experience and interest in intercalation ultimately led to the current efforts to develop small molecule therapeutic agents for myotonic dystrophy using a rational design approach that heavily relies on principles of supramolecular chemistry. How this work was influenced by that of others in the field and the evolution of each area of research is highlighted with selected examples. PMID:26877815

  6. Brain pathology in myotonic dystrophy: when tauopathy meets spliceopathy and RNAopathy

    PubMed Central

    Caillet-Boudin, Marie-Laure; Fernandez-Gomez, Francisco-Jose; Tran, Hélène; Dhaenens, Claire-Marie; Buee, Luc; Sergeant, Nicolas

    2013-01-01

    Myotonic dystrophy (DM) of type 1 and 2 (DM1 and DM2) are inherited autosomal dominant diseases caused by dynamic and unstable expanded microsatellite sequences (CTG and CCTG, respectively) in the non-coding regions of the genes DMPK and ZNF9, respectively. These mutations result in the intranuclear accumulation of mutated transcripts and the mis-splicing of numerous transcripts. This so-called RNA gain of toxic function is the main feature of an emerging group of pathologies known as RNAopathies. Interestingly, in addition to these RNA inclusions, called foci, the presence of neurofibrillary tangles (NFT) in patient brains also distinguishes DM as a tauopathy. Tauopathies are a group of nearly 30 neurodegenerative diseases that are characterized by intraneuronal protein aggregates of the microtubule-associated protein Tau (MAPT) in patient brains. Furthermore, a number of neurodegenerative diseases involve the dysregulation of splicing regulating factors and have been characterized as spliceopathies. Thus, myotonic dystrophies are pathologies resulting from the interplay among RNAopathy, spliceopathy, and tauopathy. This review will describe how these processes contribute to neurodegeneration. We will first focus on the tauopathy associated with DM1, including clinical symptoms, brain histology, and molecular mechanisms. We will also discuss the features of DM1 that are shared by other tauopathies and, consequently, might participate in the development of a tauopathy. Moreover, we will discuss the determinants common to both RNAopathies and spliceopathies that could interfere with tau-related neurodegeneration. PMID:24409116

  7. Myotonic dystrophy: HLA antigens and mitogen stimulated lymphocyte responses of a black American family.

    PubMed

    Hsia, S; Ho, C K; Aliffi, V B; Doran, D M; Hamilton, D

    1982-01-01

    A Black American family of four generations with 29 members was studied. Six family members spanning two generations were affected with myotonic dystrophy. HLA A, B, C and DR antigen specificities were determined for each family member using local typing trays. Twelve HLA haplotypes were identified in the family. No significant association was found between the disease and any HLA antigenic type or haplotype. This finding suggests that the involvement of the major histocompatibility complex in the etiology of myotonic dystrophy is unlikely. The cellular responses to twenty-eight family members and 20 unrelated Black Americans to phytohemagglutinin (PHA), Concanavalin A (Con A) and pokeweed mitogen (PWM), each in three concentrations, were tested with mononuclear cells prepared from peripheral blood. There was a significant difference in responses of the affected family members as compared to the unaffected family members and the unrelated Black Americans. The PHA and PWM responses of the unaffected family members are not significantly different from those of the unrelated Black American controls; however, the Con A responses of the unaffected family members are significantly higher than those of the control group at the lowest Con A dosage. The possible systemic defects of cytoskeletal structures of the affected family members are discussed.

  8. Dose-Dependent Regulation of Alternative Splicing by MBNL Proteins Reveals Biomarkers for Myotonic Dystrophy

    PubMed Central

    Struck, Adam J.; Gupta, Riti; Farnsworth, Dylan R.; Mahady, Amy E.; Eichinger, Katy; Thornton, Charles A.; Wang, Eric T.; Berglund, J. Andrew

    2016-01-01

    Alternative splicing is a regulated process that results in expression of specific mRNA and protein isoforms. Alternative splicing factors determine the relative abundance of each isoform. Here we focus on MBNL1, a splicing factor misregulated in the disease myotonic dystrophy. By altering the concentration of MBNL1 in cells across a broad dynamic range, we show that different splicing events require different amounts of MBNL1 for half-maximal response, and respond more or less steeply to MBNL1. Motifs around MBNL1 exon 5 were studied to assess how cis-elements mediate the MBNL1 dose-dependent splicing response. A framework was developed to estimate MBNL concentration using splicing responses alone, validated in the cell-based model, and applied to myotonic dystrophy patient muscle. Using this framework, we evaluated the ability of individual and combinations of splicing events to predict functional MBNL concentration in human biopsies, as well as their performance as biomarkers to assay mild, moderate, and severe cases of DM. PMID:27681373

  9. Analysis of meiotic segregation, using single-sperm typing: Meiotic drive at the myotonic dystrophy locus

    SciTech Connect

    Leeflang, E.P.; Arnheim, N.; McPeek, M.S.

    1996-10-01

    Meiotic drive at the myotonic dystrophy (DM) locus has recently been suggested as being responsible for maintaining the frequency, in the human population, of DM chromosomes capable of expansion to the disease state. In order to test this hypothesis, we have studied samples of single sperm from three individuals heterozygous at the DM locus, each with one allele larger and one allele smaller than 19 CTG repeats. To guard against the possible problem of differential PCR amplification rates based on the lengths of the alleles, the sperm were also typed at another closely linked marker whose allele size was unrelated to the allele size at the DM locus. Using statistical models specifically designed to study single-sperm segregation data, we find no evidence of meiotic segregation distortion. The upper limit of the two-sided 95% confidence interval for the estimate of the common segregation probability for the three donors is at or below .515 for all models considered, and no statistically significant difference from .5 is detected in any of the models. This suggests that any greater amount of segregation distortion at the myotonic dystrophy locus must result from events following sperm ejaculation. The mathematical models developed make it possible to study segregation distortion with high resolution by using sperm-typing data from any locus. 26 refs., 1 fig., 8 tabs.

  10. Mexiletine is an effective antimyotonia treatment in myotonic dystrophy type 1(LOE Classification)

    PubMed Central

    Logigian, E.L.; Martens, W.B.; Moxley, R.T.; McDermott, M.P.; Dilek, N.; Wiegner, A.W.; Pearson, A.T.; Barbieri, C.A.; Annis, C.L.; Thornton, C.A.; Moxley, R.T.

    2010-01-01

    Objective: To determine if mexiletine is safe and effective in reducing myotonia in myotonic dystrophy type 1 (DM1). Background: Myotonia is an early, prominent symptom in DM1 and contributes to decreased dexterity, gait instability, difficulty with speech/swallowing, and muscle pain. A few preliminary trials have suggested that the antiarrhythmic drug mexiletine is useful, symptomatic treatment for nondystrophic myotonic disorders and DM1. Methods: We performed 2 randomized, double-blind, placebo-controlled crossover trials, each involving 20 ambulatory DM1 participants with grip or percussion myotonia on examination. The initial trial compared 150 mg of mexiletine 3 times daily to placebo, and the second trial compared 200 mg of mexiletine 3 times daily to placebo. Treatment periods were 7 weeks in duration separated by a 4- to 8-week washout period. The primary measure of myotonia was time for isometric grip force to relax from 90% to 5% of peak force after a 3-second maximum grip contraction. EKG measurements and adverse events were monitored in both trials. Results: There was a significant reduction in grip relaxation time with both 150 and 200 mg dosages of mexiletine. Treatment with mexiletine at either dosage was not associated with any serious adverse events, or with prolongation of the PR or QTc intervals or of QRS duration. Mild adverse events were observed with both placebo and mexiletine treatment. Conclusions: Mexiletine at dosages of 150 and 200 mg 3 times daily is effective, safe, and well-tolerated over 7 weeks as an antimyotonia treatment in DM1. Classification of Evidence: This study provides Class I evidence that mexiletine at dosages of 150 and 200 mg 3 times daily over 7 weeks is well-tolerated and effective in reducing handgrip relaxation time in DM1. GLOSSARY DM1 = myotonic dystrophy type 1; MVIC = maximal voluntary isometric contraction; PF = peak force; RT = relaxation time; TID = 3 times daily. PMID:20439846

  11. Definition of regulatory sequence elements in the promoter region and the first intron of the myotonic dystrophy protein kinase gene.

    PubMed

    Storbeck, C J; Sabourin, L A; Waring, J D; Korneluk, R G

    1998-04-10

    Myotonic dystrophy is the most common inherited adult neuromuscular disorder with a global frequency of 1/8000. The genetic defect is an expanding CTG trinucleotide repeat in the 3'-untranslated region of the myotonic dystrophy protein kinase gene. We present the in vitro characterization of cis regulatory elements controlling transcription of the myotonic dystrophy protein kinase gene in myoblasts and fibroblasts. The region 5' to the initiating ATG contains no consensus TATA or CCAAT box. We have mapped two transcriptional start sites by primer extension. Deletion constructs from this region fused to the bacterial chloramphenicol acetyltransferase reporter gene revealed only subtle muscle specific cis elements. The strongest promoter activity mapped to a 189-base pair fragment. This sequence contains a conserved GC box to which the transcription factor Sp1 binds. Reporter gene constructs containing a 2-kilobase pair first intron fragment of the myotonic dystrophy protein kinase gene enhances reporter activity up to 6-fold in the human rhabdomyosarcoma myoblast cell line TE32 but not in NIH 3T3 fibroblasts. Co-transfection of a MyoD expression vector with reporter constructs containing the first intron into 10 T1/2 fibroblasts resulted in a 10-20-fold enhancement of expression. Deletion analysis of four E-box elements within the first intron reveal that these elements contribute to enhancer activity similarly in TE32 myoblasts and 10 T1/2 fibroblasts. These data suggest that E-boxes within the myotonic dystrophy protein kinase first intron mediate interactions with upstream promoter elements to up-regulate transcription of this gene in myoblasts.

  12. Parental age effects, but no evidence for an intrauterine effect in the transmission of myotonic dystrophy type 1

    PubMed Central

    Morales, Fernando; Vásquez, Melissa; Cuenca, Patricia; Campos, Domingo; Santamaría, Carolina; del Valle, Gerardo; Brian, Roberto; Sittenfeld, Mauricio; Monckton, Darren G

    2015-01-01

    Myotonic dystrophy type 1 (DM1) is caused by the expansion of an unstable CTG repeat (g.17294_17296(45_1000)) with more repeats associated with increased disease severity and reduced age at onset. Expanded disease-associated alleles are highly unstable in both the germline and soma. Germline instability is expansion biased, providing a molecular explanation for anticipation. Somatic instability is expansion biased, size- and age-dependent, features that have compromised genotype–phenotype correlations and intergenerational studies. We corrected these confounding factors by estimating the progenitor allele length in 54 father–offspring and 52 mother–offspring pairs in Costa Rican DM1 families. Not surprisingly, we found major parental allele length effects on the size of the allele transmitted, the magnitude of the intergenerational length change, the age at onset in the next generation and the degree of anticipation in both male and female transmissions. We also detected, for the first time, an age-of-parent effect for both male and female transmission. Interestingly, we found no evidence for an intrauterine effect in the transmission of congenital DM1, suggesting previous reports may have been an artefact of age-dependent somatic instability and sampling bias. These data provide new insights into the germline dynamics of the CTG repeat and opportunities for providing additional advice and more accurate risk assessments to prospective parents in DM1 families. PMID:25052313

  13. Modifications to toxic CUG RNAs induce structural stability, rescue mis-splicing in a myotonic dystrophy cell model and reduce toxicity in a myotonic dystrophy zebrafish model

    DOE PAGESBeta

    deLorimier, Elaine; Coonrod, Leslie A.; Copperman, Jeremy; Taber, Alex; Reister, Emily E.; Sharma, Kush; Todd, Peter K.; Guenza, Marina G.; Berglund, J. Andrew

    2014-10-10

    In this study, CUG repeat expansions in the 3' UTR of dystrophia myotonica protein kinase (DMPK) cause myotonic dystrophy type 1 (DM1). As RNA, these repeats elicit toxicity by sequestering splicing proteins, such as MBNL1, into protein–RNA aggregates. Structural studies demonstrate that CUG repeats can form A-form helices, suggesting that repeat secondary structure could be important in pathogenicity. To evaluate this hypothesis, we utilized structure-stabilizing RNA modifications pseudouridine (Ψ) and 2'-O-methylation to determine if stabilization of CUG helical conformations affected toxicity. CUG repeats modified with Ψ or 2'-O-methyl groups exhibited enhanced structural stability and reduced affinity for MBNL1. Molecular dynamicsmore » and X-ray crystallography suggest a potential water-bridging mechanism for Ψ-mediated CUG repeat stabilization. Ψ modification of CUG repeats rescued mis-splicing in a DM1 cell model and prevented CUG repeat toxicity in zebrafish embryos. This study indicates that the structure of toxic RNAs has a significant role in controlling the onset of neuromuscular diseases.« less

  14. Modifications to toxic CUG RNAs induce structural stability, rescue mis-splicing in a myotonic dystrophy cell model and reduce toxicity in a myotonic dystrophy zebrafish model

    SciTech Connect

    deLorimier, Elaine; Coonrod, Leslie A.; Copperman, Jeremy; Taber, Alex; Reister, Emily E.; Sharma, Kush; Todd, Peter K.; Guenza, Marina G.; Berglund, J. Andrew

    2014-10-10

    In this study, CUG repeat expansions in the 3' UTR of dystrophia myotonica protein kinase (DMPK) cause myotonic dystrophy type 1 (DM1). As RNA, these repeats elicit toxicity by sequestering splicing proteins, such as MBNL1, into protein–RNA aggregates. Structural studies demonstrate that CUG repeats can form A-form helices, suggesting that repeat secondary structure could be important in pathogenicity. To evaluate this hypothesis, we utilized structure-stabilizing RNA modifications pseudouridine (Ψ) and 2'-O-methylation to determine if stabilization of CUG helical conformations affected toxicity. CUG repeats modified with Ψ or 2'-O-methyl groups exhibited enhanced structural stability and reduced affinity for MBNL1. Molecular dynamics and X-ray crystallography suggest a potential water-bridging mechanism for Ψ-mediated CUG repeat stabilization. Ψ modification of CUG repeats rescued mis-splicing in a DM1 cell model and prevented CUG repeat toxicity in zebrafish embryos. This study indicates that the structure of toxic RNAs has a significant role in controlling the onset of neuromuscular diseases.

  15. Modifications to toxic CUG RNAs induce structural stability, rescue mis-splicing in a myotonic dystrophy cell model and reduce toxicity in a myotonic dystrophy zebrafish model.

    PubMed

    deLorimier, Elaine; Coonrod, Leslie A; Copperman, Jeremy; Taber, Alex; Reister, Emily E; Sharma, Kush; Todd, Peter K; Guenza, Marina G; Berglund, J Andrew

    2014-11-10

    CUG repeat expansions in the 3' UTR of dystrophia myotonica protein kinase (DMPK) cause myotonic dystrophy type 1 (DM1). As RNA, these repeats elicit toxicity by sequestering splicing proteins, such as MBNL1, into protein-RNA aggregates. Structural studies demonstrate that CUG repeats can form A-form helices, suggesting that repeat secondary structure could be important in pathogenicity. To evaluate this hypothesis, we utilized structure-stabilizing RNA modifications pseudouridine (Ψ) and 2'-O-methylation to determine if stabilization of CUG helical conformations affected toxicity. CUG repeats modified with Ψ or 2'-O-methyl groups exhibited enhanced structural stability and reduced affinity for MBNL1. Molecular dynamics and X-ray crystallography suggest a potential water-bridging mechanism for Ψ-mediated CUG repeat stabilization. Ψ modification of CUG repeats rescued mis-splicing in a DM1 cell model and prevented CUG repeat toxicity in zebrafish embryos. This study indicates that the structure of toxic RNAs has a significant role in controlling the onset of neuromuscular diseases. PMID:25303993

  16. The effect of myotonic dystrophy transcript levels and location on muscle differentiation

    SciTech Connect

    Mastroyiannopoulos, Nikolaos P.; Chrysanthou, Elina; Kyriakides, Tassos C.; Uney, James B.; Mahadevan, Mani S.; Phylactou, Leonidas A.

    2008-12-12

    In myotonic dystrophy type I (DM1), nuclear retention of mutant DMPK transcripts compromises muscle cell differentiation. Although several reports have identified molecular defects in myogenesis, it remains still unclear how exactly the retention of the mutant transcripts induces this defect. We have recently created a novel cellular model in which the mutant DMPK 3' UTR transcripts were released to the cytoplasm of myoblasts by using the WPRE genetic element. As a result, muscle cell differentiation was repaired. In this paper, this cellular model was further exploited to investigate the effect of the levels and location of the mutant transcripts on muscle differentiation. Results show that the levels of these transcripts were proportional to the inhibition of both the initial fusion of myoblasts and the maturity of myotubes. Moreover, the cytoplasmic export of the mutant RNAs to the cytoplasm caused less inhibition only in the initial fusion of myoblasts.

  17. Lower limb muscle impairment in myotonic dystrophy type 1: the need for better guidelines.

    PubMed

    Petitclerc, Émilie; Hébert, Luc J; Desrosiers, Johanne; Gagnon, Cynthia

    2015-04-01

    In myotonic dystrophy type 1 (DM1), leg muscle weakness is a major impairment. There are challenges to obtaining a clear portrait of muscle strength impairment. A systematic literature review was conducted on lower limb strength impairment in late-onset and adult phenotypes to document variables which affect strength measurement. Thirty-two articles were reviewed using the COSMIN guidelines. Only a third of the studies described a reproducible protocol. Only 2 muscle groups have documented reliability for quantitative muscle testing and only 1 total score for manual muscle testing. Variables affecting muscle strength impairment are not described in most studies. This review illustrates the variability in muscle strength assessment in relation to DM1 characteristics and the questionable validity of the results with regard to undocumented methodological properties. There is therefore a clear need to adopt a consensus on the use of a standardized muscle strength assessment protocol.

  18. Therapeutic impact of systemic AAV-mediated RNA interference in a mouse model of myotonic dystrophy

    PubMed Central

    Bisset, Darren R.; Stepniak-Konieczna, Ewa A.; Zavaljevski, Maja; Wei, Jessica; Carter, Gregory T.; Weiss, Michael D.; Chamberlain, Joel R.

    2015-01-01

    RNA interference (RNAi) offers a promising therapeutic approach for dominant genetic disorders that involve gain-of-function mechanisms. One candidate disease for RNAi therapy application is myotonic dystrophy type 1 (DM1), which results from toxicity of a mutant mRNA. DM1 is caused by expansion of a CTG repeat in the 3′ UTR of the DMPK gene. The expression of DMPK mRNA containing an expanded CUG repeat (CUGexp) leads to defects in RNA biogenesis and turnover. We designed miRNA-based RNAi hairpins to target the CUGexp mRNA in the human α-skeletal muscle actin long-repeat (HSALR) mouse model of DM1. RNAi expression cassettes were delivered to HSALR mice using recombinant adeno-associated viral (rAAV) vectors injected intravenously as a route to systemic gene therapy. Vector delivery significantly reduced disease pathology in muscles of the HSALR mice, including a reduction in the CUGexp mRNA, a reduction in myotonic discharges, a shift toward adult pre-mRNA splicing patterns, reduced myofiber hypertrophy and a decrease in myonuclear foci containing the CUGexp mRNA. Significant reversal of hallmarks of DM1 in the rAAV RNAi-treated HSALR mice indicate that defects characteristic of DM1 can be mitigated with a systemic RNAi approach targeting the nuclei of terminally differentiated myofibers. Efficient rAAV-mediated delivery of RNAi has the potential to provide a long-term therapy for DM1 and other dominant muscular dystrophies. PMID:26082468

  19. Two high throughput screening assays for Aberrant RNA-protein interactions in Myotonic Dystrophy Type-1

    PubMed Central

    Chen, Catherine Z.; Sobczak, Krzysztof; Hoskins, Jason; Southall, Noel; Marugan, Juan J.; Zheng, Wei; Thornton, Charles A.; Austin, Christopher P.

    2012-01-01

    Myotonic dystrophy type-1 (DM1), the most prevalent form of adult muscular dystrophy, is caused by expansion of a CTG repeat in the 3′ untranslated region of the DM protein kinase (DMPK) gene. The pathogenic effects of the CTG expansion arise from the deleterious effects of the mutant transcript. RNA with expanded CUG tracts alters the activities of several RNA binding proteins, including muscleblind-like 1 (MBNL1). MBNL1 becomes sequestered in nuclear foci in complex with the expanded CUG repeat RNA. The resulting loss of MBNL1 activity causes mis-regulated alternative splicing of multiple genes, leading to symptoms of DM1. The binding interaction between MBNL1 and mutant RNA could be a key step in the pathogenesis of DM1 and serves as a potential target for therapeutic intervention. We have developed two high throughput screen (HTS) suitable assays using both homogenous time-resolved fluorescence energy transfer (HTRF) and AlphaScreen technologies to detect the binding of a C-terminally His-tagged MBNL1 and a biotinylated (CUG)12 RNA. These assays are homogenous and successfully miniaturized to 1536-well plate format. Both assays were validated and show robust signal-to-basal ratios and Z’ factors. PMID:22218462

  20. Splicing misregulation of SCN5A contributes to cardiac-conduction delay and heart arrhythmia in myotonic dystrophy

    PubMed Central

    Freyermuth, Fernande; Rau, Frédérique; Kokunai, Yosuke; Linke, Thomas; Sellier, Chantal; Nakamori, Masayuki; Kino, Yoshihiro; Arandel, Ludovic; Jollet, Arnaud; Thibault, Christelle; Philipps, Muriel; Vicaire, Serge; Jost, Bernard; Udd, Bjarne; Day, John W.; Duboc, Denis; Wahbi, Karim; Matsumura, Tsuyoshi; Fujimura, Harutoshi; Mochizuki, Hideki; Deryckere, François; Kimura, Takashi; Nukina, Nobuyuki; Ishiura, Shoichi; Lacroix, Vincent; Campan-Fournier, Amandine; Navratil, Vincent; Chautard, Emilie; Auboeuf, Didier; Horie, Minoru; Imoto, Keiji; Lee, Kuang-Yung; Swanson, Maurice S.; de Munain, Adolfo Lopez; Inada, Shin; Itoh, Hideki; Nakazawa, Kazuo; Ashihara, Takashi; Wang, Eric; Zimmer, Thomas; Furling, Denis; Takahashi, Masanori P.; Charlet-Berguerand, Nicolas

    2016-01-01

    Myotonic dystrophy (DM) is caused by the expression of mutant RNAs containing expanded CUG repeats that sequester muscleblind-like (MBNL) proteins, leading to alternative splicing changes. Cardiac alterations, characterized by conduction delays and arrhythmia, are the second most common cause of death in DM. Using RNA sequencing, here we identify novel splicing alterations in DM heart samples, including a switch from adult exon 6B towards fetal exon 6A in the cardiac sodium channel, SCN5A. We find that MBNL1 regulates alternative splicing of SCN5A mRNA and that the splicing variant of SCN5A produced in DM presents a reduced excitability compared with the control adult isoform. Importantly, reproducing splicing alteration of Scn5a in mice is sufficient to promote heart arrhythmia and cardiac-conduction delay, two predominant features of myotonic dystrophy. In conclusion, misregulation of the alternative splicing of SCN5A may contribute to a subset of the cardiac dysfunctions observed in myotonic dystrophy. PMID:27063795

  1. Splicing misregulation of SCN5A contributes to cardiac-conduction delay and heart arrhythmia in myotonic dystrophy.

    PubMed

    Freyermuth, Fernande; Rau, Frédérique; Kokunai, Yosuke; Linke, Thomas; Sellier, Chantal; Nakamori, Masayuki; Kino, Yoshihiro; Arandel, Ludovic; Jollet, Arnaud; Thibault, Christelle; Philipps, Muriel; Vicaire, Serge; Jost, Bernard; Udd, Bjarne; Day, John W; Duboc, Denis; Wahbi, Karim; Matsumura, Tsuyoshi; Fujimura, Harutoshi; Mochizuki, Hideki; Deryckere, François; Kimura, Takashi; Nukina, Nobuyuki; Ishiura, Shoichi; Lacroix, Vincent; Campan-Fournier, Amandine; Navratil, Vincent; Chautard, Emilie; Auboeuf, Didier; Horie, Minoru; Imoto, Keiji; Lee, Kuang-Yung; Swanson, Maurice S; Lopez de Munain, Adolfo; Inada, Shin; Itoh, Hideki; Nakazawa, Kazuo; Ashihara, Takashi; Wang, Eric; Zimmer, Thomas; Furling, Denis; Takahashi, Masanori P; Charlet-Berguerand, Nicolas

    2016-01-01

    Myotonic dystrophy (DM) is caused by the expression of mutant RNAs containing expanded CUG repeats that sequester muscleblind-like (MBNL) proteins, leading to alternative splicing changes. Cardiac alterations, characterized by conduction delays and arrhythmia, are the second most common cause of death in DM. Using RNA sequencing, here we identify novel splicing alterations in DM heart samples, including a switch from adult exon 6B towards fetal exon 6A in the cardiac sodium channel, SCN5A. We find that MBNL1 regulates alternative splicing of SCN5A mRNA and that the splicing variant of SCN5A produced in DM presents a reduced excitability compared with the control adult isoform. Importantly, reproducing splicing alteration of Scn5a in mice is sufficient to promote heart arrhythmia and cardiac-conduction delay, two predominant features of myotonic dystrophy. In conclusion, misregulation of the alternative splicing of SCN5A may contribute to a subset of the cardiac dysfunctions observed in myotonic dystrophy. PMID:27063795

  2. Congenital, hypotonic-sclerotic muscular dystrophy.

    PubMed Central

    Furukawa, T; Toyokura, Y

    1977-01-01

    Four cases of congenital, hypotonic-sclerotic muscular dystrophy are presented. The patients showed clinically prominent features described by Ullrich, i.e. congenital muscle weakness, hypotonia, and hyperextensibility of distal joints, contractures of proximal joints, high-arched palate, hyperhidrosis, posterior protrusion of calcaneus, and no progression. Muscle biopsies revealed dystrophic changes. Ullrich suggested that this condition was a new entity, but the disease has received little attention. In the present cases superior intelligence and tendency to recurrent upper respiratory tract infections were stressed as characteristics of this disorder. Insufficient cellular immunity was suspected and this may contribute to the recurrent upper respiratory tract infections and pneumonia often observed. This disease is considered a distinct entity of multisystemic involvement inherited as an autosomal recessive trait. Images PMID:604494

  3. Myotonic dystrophy in Quebec: geographical distribution and concept of genetic homogeneity.

    PubMed

    Laberge, C

    1989-02-01

    The geographical distribution relative to place of residence of patients with myotonic dystrophy (MD) and admitted to a Quebec hospital during a five year period (1980-1984) is presented and discussed. The sample consists of 72 males and 68 females of varying ages over 10 years. Analysis of the data shows a North Shore distribution of patients in a cline from Saguenay-Lac-St-Jean, through Québec City and to Montréal. However, a low prevalence is apparent on the South Shore, east of Québec City, for which an historical and genealogical explanation are discussed. This geographic distribution favours the hypothesis of genetic homogeneity for the MD gene in the Québec population. A stronger second argument comes from genealogical studies of 10 families sampled from the Chicoutimi Muscular Dystrophy Clinic. Genealogical paths traced to ancestors who founded Charlevoix for these 10 families go back to a cluster of 25 founders, one of whom must have been the carrier of the MD gene. The probative third argument for genetic homogeneity comes from the allelic distribution of the apolipoprotein E (ApoE) gene in the Québec City, Saguenay and in families with MD. The ApoE locus is on chromosome 19 and closely linked to MD. In MD-affected individuals there is a linkage disequilibrium for the epsilon 4 allele while non-MD members of these families show allelic frequencies not differing significantly from the control population.(ABSTRACT TRUNCATED AT 250 WORDS)

  4. Short antisense-locked nucleic acids (all-LNAs) correct alternative splicing abnormalities in myotonic dystrophy

    PubMed Central

    Wojtkowiak-Szlachcic, Agnieszka; Taylor, Katarzyna; Stepniak-Konieczna, Ewa; Sznajder, Lukasz J.; Mykowska, Agnieszka; Sroka, Joanna; Thornton, Charles A.; Sobczak, Krzysztof

    2015-01-01

    Myotonic dystrophy type 1 (DM1) is an autosomal dominant multisystemic disorder caused by expansion of CTG triplet repeats in 3′-untranslated region of DMPK gene. The pathomechanism of DM1 is driven by accumulation of toxic transcripts containing expanded CUG repeats (CUGexp) in nuclear foci which sequester several factors regulating RNA metabolism, such as Muscleblind-like proteins (MBNLs). In this work, we utilized very short chemically modified antisense oligonucleotides composed exclusively of locked nucleic acids (all-LNAs) complementary to CUG repeats, as potential therapeutic agents against DM1. Our in vitro data demonstrated that very short, 8- or 10-unit all-LNAs effectively bound the CUG repeat RNA and prevented the formation of CUGexp/MBNL complexes. In proliferating DM1 cells as well as in skeletal muscles of DM1 mouse model the all-LNAs induced the reduction of the number and size of CUGexp foci and corrected MBNL-sensitive alternative splicing defects with high efficacy and specificity. The all-LNAs had low impact on the cellular level of CUGexp-containing transcripts and did not affect the expression of other transcripts with short CUG repeats. Our data strongly indicate that short all-LNAs complementary to CUG repeats are a promising therapeutic tool against DM1. PMID:25753670

  5. Electromechanical delay components during skeletal muscle contraction and relaxation in patients with myotonic dystrophy type 1.

    PubMed

    Esposito, Fabio; Cè, Emiliano; Rampichini, Susanna; Limonta, Eloisa; Venturelli, Massimo; Monti, Elena; Bet, Luciano; Fossati, Barbara; Meola, Giovanni

    2016-01-01

    The electromechanical delay during muscle contraction and relaxation can be partitioned into mainly electrochemical and mainly mechanical components by an EMG, mechanomyographic, and force combined approach. Component duration and measurement reliability were investigated during contraction and relaxation in a group of patients with myotonic dystrophy type 1 (DM1, n = 13) and in healthy controls (n = 13). EMG, mechanomyogram, and force were recorded in DM1 and in age- and body-matched controls from tibialis anterior (distal muscle) and vastus lateralis (proximal muscle) muscles during maximum voluntary and electrically-evoked isometric contractions. The electrochemical and mechanical components of the electromechanical delay during muscle contraction and relaxation were calculated off-line. Maximum strength was significantly lower in DM1 than in controls under both experimental conditions. All electrochemical and mechanical components were significantly longer in DM1 in both muscles. Measurement reliability was very high in both DM1 and controls. The high reliability of the measurements and the differences between DM1 patients and controls suggest that the EMG, mechanomyographic, and force combined approach could be utilized as a valid tool to assess the level of neuromuscular dysfunction in this pathology, and to follow the efficacy of pharmacological or non-pharmacological interventions.

  6. Increased autophagy and apoptosis contribute to muscle atrophy in a myotonic dystrophy type 1 Drosophila model

    PubMed Central

    Bargiela, Ariadna; Cerro-Herreros, Estefanía; Fernandez-Costa, Juan M.; Vilchez, Juan J.; Llamusi, Beatriz; Artero, Ruben

    2015-01-01

    ABSTRACT Muscle mass wasting is one of the most debilitating symptoms of myotonic dystrophy type 1 (DM1) disease, ultimately leading to immobility, respiratory defects, dysarthria, dysphagia and death in advanced stages of the disease. In order to study the molecular mechanisms leading to the degenerative loss of adult muscle tissue in DM1, we generated an inducible Drosophila model of expanded CTG trinucleotide repeat toxicity that resembles an adult-onset form of the disease. Heat-shock induced expression of 480 CUG repeats in adult flies resulted in a reduction in the area of the indirect flight muscles. In these model flies, reduction of muscle area was concomitant with increased apoptosis and autophagy. Inhibition of apoptosis or autophagy mediated by the overexpression of DIAP1, mTOR (also known as Tor) or muscleblind, or by RNA interference (RNAi)-mediated silencing of autophagy regulatory genes, achieved a rescue of the muscle-loss phenotype. In fact, mTOR overexpression rescued muscle size to a size comparable to that in control flies. These results were validated in skeletal muscle biopsies from DM1 patients in which we found downregulated autophagy and apoptosis repressor genes, and also in DM1 myoblasts where we found increased autophagy. These findings provide new insights into the signaling pathways involved in DM1 disease pathogenesis. PMID:26092529

  7. How genetics affects the brain to produce higher-level dysfunctions in myotonic dystrophy type 1

    PubMed Central

    Serra, Laura; Petrucci, Antonio; Spanò, Barbara; Torso, Mario; Olivito, Giusy; Lispi, Ludovico; Costanzi-Porrini, Sandro; Giulietti, Giovanni; Koch, Giacomo; Giacanelli, Manlio; Caltagirone, Carlo; Cercignani, Mara; Bozzali, Marco

    2015-01-01

    Summary Myotonic dystrophy type 1 (DM1) is a multisystemic disorder dominated by muscular impairment and brain dysfunctions. Although brain damage has previously been demonstrated in DM1, its associations with the genetics and clinical/neuropsychological features of the disease are controversial. This study assessed the differential role of gray matter (GM) and white matter (WM) damage in determining higher-level dysfunctions in DM1. Ten patients with genetically confirmed DM1 and 16 healthy matched controls entered the study. The patients underwent a neuropsychological assessment and quantification of CTG triplet expansion. All the subjects underwent MR scanning at 3T, with studies including T1-weighted volumes and diffusion-weighted images. Voxel-based morphometry and tract-based spatial statistics were used for unbiased quantification of regional GM atrophy and WM integrity. The DM1 patients showed widespread involvement of both tissues. The extent of the damage correlated with CTG triplet expansion and cognition. This study supports the idea that genetic abnormalities in DM1 mainly target the WM, but GM involvement is also crucial in determining the clinical characteristics of DM1. PMID:26214024

  8. Swallowing assessment in myotonic dystrophy type 1 using fiberoptic endoscopic evaluation of swallowing (FEES).

    PubMed

    Pilz, Walmari; Baijens, Laura W J; Passos, Valéria Lima; Verdonschot, Rob; Wesseling, Frederik; Roodenburg, Nel; Faber, Catharina G; Kremer, Bernd

    2014-12-01

    This study describes the swallowing function of patients with myotonic dystrophy type 1 (DM1) and the effect of bolus consistency on swallowing in this group. The aim of the study is twofold: (a) to identify which (and to what extent) swallowing variables change for DM1 patients relative to healthy control subjects and (b) to examine whether the degree of oropharyngeal dysphagia is associated with disease severity. Forty-five consecutive DM1 patients and ten healthy subjects underwent a swallowing assessment, at Maastricht University medical Center in the Netherlands. The assessment included a standardized fiberoptic endoscopic evaluation of swallowing (FEES) protocol using different bolus consistencies. Clinical severity of the disease was assessed using the muscular impairment rating scale (MIRS). Significant differences were found between patients and controls for all FEES variables. The magnitude of these differences depended on the bolus consistency. The odds of a more pathological swallowing outcome increased significantly with higher MIRS levels. In conclusion, swallowing function is found to be significantly altered in DM1 patients. The results emphasize the importance of conducting a detailed swallowing assessment in all patients, even those with mild muscle weakness.

  9. Six Serum miRNAs Fail to Validate as Myotonic Dystrophy Type 1 Biomarkers

    PubMed Central

    Fernandez-Costa, Juan M.; Llamusi, Beatriz; Bargiela, Ariadna; Zulaica, Miren; Alvarez-Abril, M. Carmen; Perez-Alonso, Manuel; Lopez de Munain, Adolfo

    2016-01-01

    Myotonic dystrophy type 1 (DM1) is an autosomal dominant genetic disease caused by expansion of a CTG microsatellite in the 3’ untranslated region of the DMPK gene. Despite characteristic muscular, cardiac, and neuropsychological symptoms, CTG trinucleotide repeats are unstable both in the somatic and germinal lines, making the age of onset, clinical presentation, and disease severity very variable. A molecular biomarker to stratify patients and to follow disease progression is, thus, an unmet medical need. Looking for a novel biomarker, and given that specific miRNAs have been found to be misregulated in DM1 heart and muscle tissues, we profiled the expression of 175 known serum miRNAs in DM1 samples. The differences detected between patients and controls were less than 2.6 fold for all of them and a selection of six candidate miRNAs, miR-103, miR-107, miR-21, miR-29a, miR-30c, and miR-652 all failed to show consistent differences in serum expression in subsequent validation experiments. PMID:26919350

  10. Six Serum miRNAs Fail to Validate as Myotonic Dystrophy Type 1 Biomarkers.

    PubMed

    Fernandez-Costa, Juan M; Llamusi, Beatriz; Bargiela, Ariadna; Zulaica, Miren; Alvarez-Abril, M Carmen; Perez-Alonso, Manuel; Lopez de Munain, Adolfo; Lopez-Castel, Arturo; Artero, Ruben

    2016-01-01

    Myotonic dystrophy type 1 (DM1) is an autosomal dominant genetic disease caused by expansion of a CTG microsatellite in the 3' untranslated region of the DMPK gene. Despite characteristic muscular, cardiac, and neuropsychological symptoms, CTG trinucleotide repeats are unstable both in the somatic and germinal lines, making the age of onset, clinical presentation, and disease severity very variable. A molecular biomarker to stratify patients and to follow disease progression is, thus, an unmet medical need. Looking for a novel biomarker, and given that specific miRNAs have been found to be misregulated in DM1 heart and muscle tissues, we profiled the expression of 175 known serum miRNAs in DM1 samples. The differences detected between patients and controls were less than 2.6 fold for all of them and a selection of six candidate miRNAs, miR-103, miR-107, miR-21, miR-29a, miR-30c, and miR-652 all failed to show consistent differences in serum expression in subsequent validation experiments. PMID:26919350

  11. Brain Connectomics' Modification to Clarify Motor and Nonmotor Features of Myotonic Dystrophy Type 1

    PubMed Central

    Serra, Laura; Mancini, Matteo; Silvestri, Gabriella; Petrucci, Antonio; Masciullo, Marcella; Spanò, Barbara; Torso, Mario; Mastropasqua, Chiara; Giacanelli, Manlio; Caltagirone, Carlo; Cercignani, Mara; Meola, Giovanni; Bozzali, Marco

    2016-01-01

    The adult form of myotonic dystrophy type 1 (DM1) presents with paradoxical inconsistencies between severity of brain damage, relative preservation of cognition, and failure in everyday life. This study, based on the assessment of brain connectivity and mechanisms of plasticity, aimed at reconciling these conflicting issues. Resting-state functional MRI and graph theoretical methods of analysis were used to assess brain topological features in a large cohort of patients with DM1. Patients, compared to controls, revealed reduced connectivity in a large frontoparietal network that correlated with their isolated impairment in visuospatial reasoning. Despite a global preservation of the topological properties, peculiar patterns of frontal disconnection and increased parietal-cerebellar connectivity were also identified in patients' brains. The balance between loss of connectivity and compensatory mechanisms in different brain networks might explain the paradoxical mismatch between structural brain damage and minimal cognitive deficits observed in these patients. This study provides a comprehensive assessment of brain abnormalities that fit well with both motor and nonmotor clinical features experienced by patients in their everyday life. The current findings suggest that measures of functional connectivity may offer the possibility of characterizing individual patients with the potential to become a clinical tool. PMID:27313901

  12. Detection of linkage disequilibrium between the myotonic dystrophy locus and a new polymorphic DNA marker.

    PubMed Central

    Harley, H G; Brook, J D; Floyd, J; Rundle, S A; Crow, S; Walsh, K V; Thibault, M C; Harper, P S; Shaw, D J

    1991-01-01

    We have examined the linkage of two new polymorphic DNA markers (D19S62 and D19S63) and a previously unreported polymorphism with an existing DNA marker (ERCC1) to the myotonic dystrophy (DM) locus. In addition, we have used pulsed-field gel electrophoresis to obtain a fine-structure map of this region. The detection of linkage disequilibrium between DM and one of these markers (D19S63) is the first demonstration of this phenomenon in a heterogeneous DM population. The results suggest that at least 58% of DM patients in the British population, as well as those in a French-Canadian subpopulation, are descended from the same ancestral DM mutation. We discuss the implications of this finding in terms of strategies for cloning the DM gene, for a possible role in modification of risk for prenatal and presymptomatic testing, and we speculate on the origin and number of existing mutations which may result in a DM phenotype. PMID:2063878

  13. Impact of Biopsychosocial Factors on Chronic Pain in Persons With Myotonic and Facioscapulohumeral Muscular Dystrophy

    PubMed Central

    Miró, Jordi; Raichle, Katherine A.; Carter, Gregory T.; O’Brien, Sarah A.; Abresch, Richard T.; McDonald, Craig M.; Jensen, Mark P.

    2010-01-01

    To assess the role of biopsychosocial factors in patients with type 1 myotonic and facioscapulohumeral muscular dystrophy (MMD1/FSHD) with chronic pain. Associations between psychosocial factors were found to be important in other samples of persons with pain and both psychological functioning and pain interference in a sample of patients suffering from MMD/FSHD. Prospective, multiple group, survey study of 182 patients with confirmed MMD1 and FSHD. Participants completed surveys assessing pain interference and psychological functioning, as well as psychosocial, demographic, and injury-related variables. Analyses indicated that greater catastrophizing was associated with increased pain interference and poorer psychological functioning, pain attitudes were significantly related to both pain interference and psychological functioning, and coping responses were significantly related only to pain interference. In addition, greater perceived social support was associated with better psychological functioning. The results support the use of studying pain in persons with MMD/FSHD from a biopsychosocial perspective, and the importance of identifying psychosocial factors that may play a role in the adjustment to and response to pain secondary to MMD/FSHD. PMID:19414560

  14. Role of Myotonic Dystrophy Protein Kinase (DMPK) in Glucose Homeostasis and Muscle Insulin Action

    PubMed Central

    Marti, Luc; Liesa, Marc; Camps, Marta; Ciaraldi, Theodore P.; Kondo, Richard; Reddy, Sita; Dillmann, Wolfgang H.; Palacin, Manuel; Zorzano, Antonio; Ruiz-Lozano, Pilar; Gomis, Ramon; Kaliman, Perla

    2007-01-01

    Myotonic dystrophy 1 (DM1) is caused by a CTG expansion in the 3′-unstranslated region of the DMPK gene, which encodes a serine/threonine protein kinase. One of the common clinical features of DM1 patients is insulin resistance, which has been associated with a pathogenic effect of the repeat expansions. Here we show that DMPK itself is a positive modulator of insulin action. DMPK-deficient (dmpk−/−) mice exhibit impaired insulin signaling in muscle tissues but not in adipocytes and liver, tissues in which DMPK is not expressed. Dmpk−/− mice display metabolic derangements such as abnormal glucose tolerance, reduced glucose uptake and impaired insulin-dependent GLUT4 trafficking in muscle. Using DMPK mutants, we show that DMPK is required for a correct intracellular trafficking of insulin and IGF-1 receptors, providing a mechanism to explain the molecular and metabolic phenotype of dmpk−/− mice. Taken together, these findings indicate that reduced DMPK expression may directly influence the onset of insulin-resistance in DM1 patients and point to dmpk as a new candidate gene for susceptibility to type 2-diabetes. PMID:17987120

  15. Impact of biopsychosocial factors on chronic pain in persons with myotonic and facioscapulohumeral muscular dystrophy.

    PubMed

    Miró, Jordi; Raichle, Katherine A; Carter, Gregory T; O'Brien, Sarah A; Abresch, Richard T; McDonald, Craig M; Jensen, Mark P

    2009-01-01

    To assess the role of biopsychosocial factors in patients with type 1 myotonic and facioscapulohumeral muscular dystrophy (MMD1/FSHD) with chronic pain. Associations between psychosocial factors were found to be important in other samples of persons with pain and both psychological functioning and pain interference in a sample of patients suffering from MMD/FSHD. Prospective, multiple group, survey study of 182 patients with confirmed MMD1 and FSHD. Participants completed surveys assessing pain interference and psychological functioning, as well as psychosocial, demographic, and injury-related variables. Analyses indicated that greater catastrophizing was associated with increased pain interference and poorer psychological functioning, pain attitudes were significantly related to both pain interference and psychological functioning, and coping responses were significantly related only to pain interference. In addition, greater perceived social support was associated with better psychological functioning. The results support the use of studying pain in persons with MMD/FSHD from a biopsychosocial perspective, and the importance of identifying psychosocial factors that may play a role in the adjustment to and response to pain secondary to MMD/FSHD. PMID:19414560

  16. Segregation distortion of the CTG repeats at the myotonic dystrophy locus

    SciTech Connect

    Chakraborty, R.; Stivers, D.N.; Deka, R.; Yu, Ling M.; Shriver, M.D.; Ferrell, R.E.

    1996-07-01

    Myotonic dystrophy (DM), an autosomal dominant neuromuscular disease, is caused by a CTG-repeat expansion, with affected individuals having {ge}50 repeats of this trinucleotide, at the DMPK locus of human chromosome 19q13.3. Severely affected individuals die early in life; the milder form of this disease reduces reproductive ability. Alleles in the normal range of CTG repeats are not as unstable as the (CTG){sub {ge}50} alleles. In the DM families, anticipation and parental bias of allelic expansions have been noted. However, data on mechanism of maintenance of DM in populations are conflicting. We present a maximum-likelihood model for examining segregation distortion of CTG-repeat alleles in normal families. Analyzing 726 meiotic events in 95 nuclear families from the CEPH panel pedigrees, we find evidence of preferential transmission of larger alleles (of size {le}29 repeats) from females (the probability of transmission of larger alleles is .565 {plus_minus} 0.03, different from .5 at P {approx} .028). There is no evidence of segregation distortion during male meiosis. We propose a hypothesis that preferential transmission of larger CTG-repeat alleles during female meiosis can compensate for mutational contraction of repeats within the normal allelic size range, and reduced viability and fertility of affected individuals. Thus, the pool of premutant alleles at the DM locus can be maintained in populations, which can subsequently mutate to the full mutation status to give rise to DM. 31 refs., 1 fig., 5 tabs.

  17. Molecular aptamer beacon for myotonic dystrophy kinase-related Cdc42-binding kinase alpha.

    PubMed

    Tok, Junie; Lai, Jesyin; Leung, Thomas; Li, Sam Fong Yau

    2010-04-15

    A novel strategy for the development of molecular aptamer beacon for a signal transduction protein, myotonic dystrophy kinase-related Cdc42-binding kinase (MRCK) was proposed in this work. MRCK is an important downstream effector protein of Cdc42 that phosphorylates proteins involved in organizing actin structures responsible for forming stress fibres, lamellipodia or filopodia. The simple method for MAB design could potentially be applied to other aptamers for modification into a protein probe. The MRCK aptamer was modified into a MAB by adding nucleotides on the 5' end, which are complementary to the 3' end of the aptamer so as to destroy the existing structure and change it into a MB form. In the absence of MRCK, the MAB remained a hairpin structure. However, in the presence of MRCK, the equilibrium was shifted towards the formation of the MRCK-aptamer complex, resulting in the preference for the MRCK-binding conformer, where a fluorescence-quenching pair added to the 5' and 3' ends signaled any protein-dependent conformation change. The development of MABs for signal transduction proteins will have the potential to replace antibodies for diagnostic assays as well as protein studies in cellular imaging.

  18. Characteristic MRI Findings of upper Limb Muscle Involvement in Myotonic Dystrophy Type 1

    PubMed Central

    Sugie, Kazuma; Sugie, Miho; Taoka, Toshio; Tonomura, Yasuyo; Kumazawa, Aya; Izumi, Tesseki; Kichikawa, Kimihiko; Ueno, Satoshi

    2015-01-01

    The objective of our study was to evaluate the relation between muscle MRI findings and upper limb weakness with grip myotonia in patients with myotonic dystrophy type 1 (DM1). Seventeen patients with DM1 were evaluated by manual muscle strength testing and muscle MRI of the upper limbs. Many DM1 patients presenting with decreased grasping power frequently showed high intensity signals in the flexor digitorum profundus (FDP) muscles on T1-weighted imaging. Patients presenting with upper limb weakness frequently also showed high intensity signals in the flexor pollicis longus, abductor pollicis longus, and extensor pollicis muscles. Disturbances of the distal muscles of the upper limbs were predominant in all DM1 patients. Some DM1 patients with a prolonged disease duration showed involvement of not only distal muscles but also proximal muscles in the upper limbs. Muscle involvement of the upper limbs on MRI strongly correlated positively with the disease duration or the numbers of CTG repeats. To our knowledge, this is the first study to provide a detailed description of the distribution and severity of affected muscles of the upper limbs on MRI in patients with DM1. We conclude that muscle MRI findings are very useful for identifying affected muscles and predicting the risk of muscle weakness in the upper limbs of DM1 patients. PMID:25919300

  19. Congenital muscular dystrophy with inflammation: Diagnostic considerations

    PubMed Central

    Konkay, Kaumudi; Kannan, Meena Angamuthu; Lingappa, Lokesh; Uppin, Megha S.; Challa, Sundaram

    2016-01-01

    Background and Purpose: Muscle biopsy features of congenital muscular dystrophies (CMD) vary from usual dystrophic picture to normal or nonspecific myopathic picture or prominent fibrosis or striking inflammatory infiltrate, which may lead to diagnostic errors. A series of patients of CMD with significant inflammatory infiltrates on muscle biopsy were correlated with laminin α2 deficiency on immunohistochemistry (IHC). Material and Methods: Cryostat sections of muscle biopsies from the patients diagnosed as CMD on clinical and muscle biopsy features from 1996 to 2014 were reviewed with hematoxylin and eosin(H&E), enzyme and immunohistochemistry (IHC) with laminin α2. Muscle biopsies with inflammatory infiltrate were correlated with laminin α2 deficiency. Results: There were 65 patients of CMD, with inflammation on muscle biopsy in 16. IHC with laminin α2 was available in nine patients, of which six showed complete absence along sarcolemma (five presented with floppy infant syndrome and one with delayed motor milestones) and three showed discontinuous, and less intense staining. Conclusions: CMD show variable degrees of inflammation on muscle biopsy. A diagnosis of laminin α2 deficient CMD should be considered in patients of muscular dystrophy with inflammation, in children with hypotonia/delayed motor milestones. PMID:27570388

  20. Pentamidine rescues contractility and rhythmicity in a Drosophila model of myotonic dystrophy heart dysfunction.

    PubMed

    Chakraborty, Mouli; Selma-Soriano, Estela; Magny, Emile; Couso, Juan Pablo; Pérez-Alonso, Manuel; Charlet-Berguerand, Nicolas; Artero, Ruben; Llamusi, Beatriz

    2015-12-01

    Up to 80% of individuals with myotonic dystrophy type 1 (DM1) will develop cardiac abnormalities at some point during the progression of their disease, the most common of which is heart blockage of varying degrees. Such blockage is characterized by conduction defects and supraventricular and ventricular tachycardia, and carries a high risk of sudden cardiac death. Despite its importance, very few animal model studies have focused on the heart dysfunction in DM1. Here, we describe the characterization of the heart phenotype in a Drosophila model expressing pure expanded CUG repeats under the control of the cardiomyocyte-specific driver GMH5-Gal4. Morphologically, expression of 250 CUG repeats caused abnormalities in the parallel alignment of the spiral myofibrils in dissected fly hearts, as revealed by phalloidin staining. Moreover, combined immunofluorescence and in situ hybridization of Muscleblind and CUG repeats, respectively, confirmed detectable ribonuclear foci and Muscleblind sequestration, characteristic features of DM1, exclusively in flies expressing the expanded CTG repeats. Similarly to what has been reported in humans with DM1, heart-specific expression of toxic RNA resulted in reduced survival, increased arrhythmia, altered diastolic and systolic function, reduced heart tube diameters and reduced contractility in the model flies. As a proof of concept that the fly heart model can be used for in vivo testing of promising therapeutic compounds, we fed flies with pentamidine, a compound previously described to improve DM1 phenotypes. Pentamidine not only released Muscleblind from the CUG RNA repeats and reduced ribonuclear formation in the Drosophila heart, but also rescued heart arrhythmicity and contractility, and improved fly survival in animals expressing 250 CUG repeats.

  1. Pentamidine rescues contractility and rhythmicity in a Drosophila model of myotonic dystrophy heart dysfunction

    PubMed Central

    Chakraborty, Mouli; Selma-Soriano, Estela; Magny, Emile; Couso, Juan Pablo; Pérez-Alonso, Manuel; Charlet-Berguerand, Nicolas; Artero, Ruben; Llamusi, Beatriz

    2015-01-01

    ABSTRACT Up to 80% of individuals with myotonic dystrophy type 1 (DM1) will develop cardiac abnormalities at some point during the progression of their disease, the most common of which is heart blockage of varying degrees. Such blockage is characterized by conduction defects and supraventricular and ventricular tachycardia, and carries a high risk of sudden cardiac death. Despite its importance, very few animal model studies have focused on the heart dysfunction in DM1. Here, we describe the characterization of the heart phenotype in a Drosophila model expressing pure expanded CUG repeats under the control of the cardiomyocyte-specific driver GMH5-Gal4. Morphologically, expression of 250 CUG repeats caused abnormalities in the parallel alignment of the spiral myofibrils in dissected fly hearts, as revealed by phalloidin staining. Moreover, combined immunofluorescence and in situ hybridization of Muscleblind and CUG repeats, respectively, confirmed detectable ribonuclear foci and Muscleblind sequestration, characteristic features of DM1, exclusively in flies expressing the expanded CTG repeats. Similarly to what has been reported in humans with DM1, heart-specific expression of toxic RNA resulted in reduced survival, increased arrhythmia, altered diastolic and systolic function, reduced heart tube diameters and reduced contractility in the model flies. As a proof of concept that the fly heart model can be used for in vivo testing of promising therapeutic compounds, we fed flies with pentamidine, a compound previously described to improve DM1 phenotypes. Pentamidine not only released Muscleblind from the CUG RNA repeats and reduced ribonuclear formation in the Drosophila heart, but also rescued heart arrhythmicity and contractility, and improved fly survival in animals expressing 250 CUG repeats. PMID:26515653

  2. Muscleblind, BSF and TBPH are mislocalized in the muscle sarcomere of a Drosophila myotonic dystrophy model.

    PubMed

    Llamusi, Beatriz; Bargiela, Ariadna; Fernandez-Costa, Juan M; Garcia-Lopez, Amparo; Klima, Raffaella; Feiguin, Fabian; Artero, Ruben

    2013-01-01

    Myotonic dystrophy type 1 (DM1) is a genetic disease caused by the pathological expansion of a CTG trinucleotide repeat in the 3' UTR of the DMPK gene. In the DMPK transcripts, the CUG expansions sequester RNA-binding proteins into nuclear foci, including transcription factors and alternative splicing regulators such as MBNL1. MBNL1 sequestration has been associated with key features of DM1. However, the basis behind a number of molecular and histological alterations in DM1 remain unclear. To help identify new pathogenic components of the disease, we carried out a genetic screen using a Drosophila model of DM1 that expresses 480 interrupted CTG repeats, i(CTG)480, and a collection of 1215 transgenic RNA interference (RNAi) fly lines. Of the 34 modifiers identified, two RNA-binding proteins, TBPH (homolog of human TAR DNA-binding protein 43 or TDP-43) and BSF (Bicoid stability factor; homolog of human LRPPRC), were of particular interest. These factors modified i(CTG)480 phenotypes in the fly eye and wing, and TBPH silencing also suppressed CTG-induced defects in the flight muscles. In Drosophila flight muscle, TBPH, BSF and the fly ortholog of MBNL1, Muscleblind (Mbl), were detected in sarcomeric bands. Expression of i(CTG)480 resulted in changes in the sarcomeric patterns of these proteins, which could be restored by coexpression with human MBNL1. Epistasis studies showed that Mbl silencing was sufficient to induce a subcellular redistribution of TBPH and BSF proteins in the muscle, which mimicked the effect of i(CTG)480 expression. These results provide the first description of TBPH and BSF as targets of Mbl-mediated CTG toxicity, and they suggest an important role of these proteins in DM1 muscle pathology.

  3. Correlation between distribution of muscle weakness, electrophysiological findings and CTG expansion in myotonic dystrophy.

    PubMed

    Khoshbakht, Roya; Soltanzadeh, Akbar; Zamani, Babak; Abdi, Siyamak; Gharagozli, Kourosh; Kahrizi, Kimia; Khoshbakht, Rahem; Nafissi, Shahriar

    2014-07-01

    Myotonic dystrophy type 1 (DM-1) is a multi-system disorder affecting the muscles, brain, cardiovascular system, endocrine system, eyes and skin. Diagnosis is made by clinical, electrodiagnostic and genetic studies. This study aimed to determine the correlation between CTG expansion and distribution of muscle weakness and clinical and electrophysiological findings. Genetically confirmed DM-1 patients presenting to Shariati Hospital between 2005 and 2011 were included in this study. Clinical, electrodiagnostic and genetic testing was performed and the correlation between CTG expansion and distribution of muscle weakness and clinical and electromyographic findings was studied. Thirty-three genetically confirmed DM-1 patients were enrolled. Myotonia, bifacial weakness and distal upper limb weakness were seen in all patients. Diabetes mellitus was found in one patient (3%), cardiac disturbance in eight (24.2%), cataracts in eight (24.2%), hypogonadism in five (15.2%), frontal baldness in 13 (39.4%), temporalis wasting in 14 (42.4%), temporomandibular joint disorder in seven (21.2%) and mental retardation in eight (24.2%). The mean number of CTG repeats, measured by Southern blot, was 8780 (range 500-15,833). A negative correlation was found between CTG expansion and age of onset. Temporalis wasting and mental retardation were positively correlated with CTG expansion. No relationship was found between weakness distribution, electromyographic findings, other systemic features and CTG expansion. In this study of DM-1 in Iran, we found a correlation between CTG expansion and age of onset, temporalis wasting and mental disability. No correlation between CTG expansion and electrodiagnostic and other clinical findings were detected.

  4. Identification of Plant-derived Alkaloids with Therapeutic Potential for Myotonic Dystrophy Type I.

    PubMed

    Herrendorff, Ruben; Faleschini, Maria Teresa; Stiefvater, Adeline; Erne, Beat; Wiktorowicz, Tatiana; Kern, Frances; Hamburger, Matthias; Potterat, Olivier; Kinter, Jochen; Sinnreich, Michael

    2016-08-12

    Myotonic dystrophy type I (DM1) is a disabling neuromuscular disease with no causal treatment available. This disease is caused by expanded CTG trinucleotide repeats in the 3' UTR of the dystrophia myotonica protein kinase gene. On the RNA level, expanded (CUG)n repeats form hairpin structures that sequester splicing factors such as muscleblind-like 1 (MBNL1). Lack of available MBNL1 leads to misregulated alternative splicing of many target pre-mRNAs, leading to the multisystemic symptoms in DM1. Many studies aiming to identify small molecules that target the (CUG)n-MBNL1 complex focused on synthetic molecules. In an effort to identify new small molecules that liberate sequestered MBNL1 from (CUG)n RNA, we focused specifically on small molecules of natural origin. Natural products remain an important source for drugs and play a significant role in providing novel leads and pharmacophores for medicinal chemistry. In a new DM1 mechanism-based biochemical assay, we screened a collection of isolated natural compounds and a library of over 2100 extracts from plants and fungal strains. HPLC-based activity profiling in combination with spectroscopic methods were used to identify the active principles in the extracts. The bioactivity of the identified compounds was investigated in a human cell model and in a mouse model of DM1. We identified several alkaloids, including the β-carboline harmine and the isoquinoline berberine, that ameliorated certain aspects of the DM1 pathology in these models. Alkaloids as a compound class may have potential for drug discovery in other RNA-mediated diseases. PMID:27298317

  5. CTG repeats distribution and Alu insertion polymorphism at myotonic dystrophy (DM) gene in Amhara and Oromo populations of Ethiopia.

    PubMed

    Gennarelli, M; Pavoni, M; Cruciani, F; De Stefano, G; Dallapiccola, B; Novelli, G

    1999-01-01

    Myotonic dystrophy (DM) is a dominantly inherited neuromuscular disease, highly variable and multisystemic, which is caused by the expansion of a CTG repeat located in the 3' untranslated region of the DMPK gene. Normal alleles show a copy number of 5-37 repeats on normal chromosomes, amplified to 50-3000 copies on DM chromosomes. The trinucleotide repeat shows a trimodal allele distribution in the majority of the examined population. The first class includes alleles carrying (CTG)5, the second class, alleles in the range 7-18 repeats, and the third class, alleles (CTG) > or =19. The frequency of this third class is directly related to the prevalence of DM in different populations, suggesting that normal large-sized alleles predispose toward DM. We studied CTG repeat allele distribution and Alu insertion and/or deletion polymorphism at the myotonic dystrophy locus in two major Ethiopian populations, the Amhara and Oromo. CTG allele distribution and haplotype analysis on a total of 224 normal chromosomes showed significant differences between the two ethnic groups. These differences have a bearing on the out-of-Africa hypothesis for the origin of the DM mutation. In addition, (CTG) > or =19 were exclusively detected in the Amhara population, confirming the predisposing role of these alleles compared with the DM expansion-mutation.

  6. Congenital muscular dystrophy: from muscle to brain.

    PubMed

    Falsaperla, Raffaele; Praticò, Andrea D; Ruggieri, Martino; Parano, Enrico; Rizzo, Renata; Corsello, Giovanni; Vitaliti, Giovanna; Pavone, Piero

    2016-01-01

    Congenital muscular dystrophies (CMDs) are a wide group of muscular disorders that manifest with very early onset of muscular weakness, sometime associated to severe brain involvement.The histologic pattern of muscle anomalies is typical of dystrophic lesions but quite variable depending on the different stages and on the severity of the disorder.Recent classification of CMDs have been reported most of which based on the combination of clinical, biochemical, molecular and genetic findings, but genotype/phenotype correlation are in constant progression due to more diffuse utilization of the molecular analysis.In this article, the Authors report on CMDs belonging to the group of dystroglycanopathies and in particular on the most severe forms represented by the Fukuyama CMD, Muscle-Eye-Brain disease and Walker Walburg syndrome.Clinical diagnosis of infantile hypotonia is particularly difficult considering the different etiologic factors causing the lesions, the difficulty in localizing the involved CNS area (central vs. peripheral) and the limited role of the diagnostic procedures at this early age.The diagnostic evaluation is not easy mainly in differentiating the various types of CMDs, and represents a challenge for the neonatologists and pediatricians. Suggestions are reported on the way to reach a correct diagnosis with the appropriate use of the diagnostic means. PMID:27576556

  7. Myocardial fibrosis in patients with myotonic dystrophy type 1: a cardiovascular magnetic resonance study

    PubMed Central

    2014-01-01

    Background Myotonic dystrophy type 1 (DM1) is associated with increased cardiac morbidity and mortality. Therefore, assessment of cardiac involvement and risk stratification for sudden cardiac death is crucial. Nevertheless, optimal screening-procedures are not clearly defined. ECG, echocardiography and Holter-monitoring are useful but insufficient. Cardiovascular magnetic resonance (CMR) can provide additional information of which myocardial fibrosis may be relevant. The purpose of this study was to describe the prevalence of myocardial fibrosis in patients with DM1 assessed by CMR, and the association between myocardial fibrosis and abnormal findings on ECG, Holter-monitoring and echocardiography. Methods We selected 30 unrelated patients with DM1: 18 patients (10 men, mean age 51 years) with, and 12 patients (7 men, mean age 41 years) without abnormal findings on ECG and Holter-monitoring. Patients were evaluated with medical history, physical examination, ECG, Holter-monitoring, echocardiography and CMR. Results Myocardial fibrosis was found in 12/30 (40%, 9 men). The presence of myocardial fibrosis was associated with the following CMR-parameters: increased left ventricular mass (median (range) 55 g/m2 (43–83) vs. 46 g/m2 (36–64), p = 0.02), increased left atrial volume (median (range) 52 ml/m2 (36–87) vs. 46 ml/m2 (35–69), p = 0.04) and a trend toward lower LVEF (median (range) 63% (38–71) vs. 66% (60–80), p = 0.06). Overall, we found no association between the presence of myocardial fibrosis and abnormal findings on: ECG (p = 0.71), Holter-monitoring (p = 0.27) or echocardiographic measurements of left ventricular volumes, ejection fraction or global longitudinal strain (p = 0.18). Conclusion Patients with DM1 had a high prevalence of myocardial fibrosis which was not predicted by ECG, Holter-monitoring or echocardiography. CMR add additional information to current standard cardiac assessment and may prove to be a clinically valuable tool for

  8. Overexpression of microRNA-206 in the skeletal muscle from myotonic dystrophy type 1 patients

    PubMed Central

    2010-01-01

    Background MicroRNAs are highly conserved, noncoding RNAs involved in post-transcriptional gene silencing. They have been shown to participate in a wide range of biological processes, including myogenesis and muscle regeneration. The goal of this study is to test the hypothesis that myo-miRs (myo = muscle + miR = miRNA) expression is altered in muscle from patients affected by myotonic dystrophy type 1 (DM1), the most frequently inherited neuromuscular disease in adults. In order to gain better insights about the role of miRNAs in the DM1 pathogenesis, we have also analyzed the muscular expression of miR-103 and miR-107, which have been identified in silico as attractive candidates for binding to the DMPK mRNA. Methods To this aim, we have profiled the expression of miR-133 (miR-133a, miR-133b), miR-1, miR-181 (miR-181a, miR-181b, miR-181c) and miR-206, that are specifically induced during myogenesis in cardiac and skeletal muscle tissues. miR-103 and miR-107, highly expressed in brain, heart and muscle have also been included in this study. QRT-PCR experiments have been performed on RNA from vastus lateralis biopsies of DM1 patients (n = 7) and control subjects (n = 4). Results of miRNAs expression have been confirmed by Northern blot, whereas in situ hybridization technique have been performed to localize misexpressed miRNAs on muscle sections from DM1 and control individuals. Results Only miR-206 showed an over-expression in 5 of 7 DM1 patients (threshold = 2, fold change between 1.20 and 13.22, average = 5.37) compared to the control group. This result has been further confirmed by Northern blot analysis (3.37-fold overexpression, R2 = 0.89). In situ hybridization localized miR-206 to nuclear site both in normal and DM1 tissues. Cellular distribution in DM1 tissues includes also the nuclear regions of centralized nuclei, with a strong signal corresponding to nuclear clumps. Conclusions This work provides, for the first time, evidences about miRNAs misexpression

  9. Muscleblind1, but not Dmpk or Six5, contributes to a complex phenotype of muscular and motivational deficits in mouse models of myotonic dystrophy.

    PubMed

    Matynia, Anna; Ng, Carina Hoi; Dansithong, Warunee; Chiang, Andy; Silva, Alcino J; Reddy, Sita

    2010-03-25

    Assessment of molecular defects that underlie cognitive deficits observed in mendelian disorders provides a unique opportunity to identify key regulators of human cognition. Congenital Myotonic Dystrophy 1 (cDM1), a multi-system disorder is characterized by both cognitive deficits and a spectrum of behavioral abnormalities, which include visuo-spatial memory deficits, anxiety and apathy. Decreased levels of DMPK (Dystrophia Myotonica-protein kinase), SIX5, a transcription factor or MBNL1 (Muscleblind-like 1), an RNA splice regulator have been demonstrated to contribute to distinct features of cDM1. Mouse strains in which either Dmpk, Six5 or Mbnl1 are inactivated were therefore studied to determine the relative contribution of each gene to these cognitive functions. The open field and elevated plus maze tasks were used to examine anxiety, sucrose consumption was used to assess motivation, whereas the water maze and context fear conditioning were used to examine spatial learning and memory. Cognitive and behavioral abnormalities were observed only in Mbnl1 deficient mice, which demonstrate behavior consistent with motivational deficits in the Morris water maze, a complex visuo-spatial task and in the sucrose consumption test for anhedonia. All three models of cDM1 exhibit normal spatial learning and memory. These data identify MBNL1 as a potential regulator of emotional state with decreased MBNL1 levels underlying the motivational deficits observed in cDM1.

  10. Electrodiagnosis of myotonic disorders.

    PubMed

    Hehir, Michael K; Logigian, Eric L

    2013-02-01

    Clinical and electrical myotonia is caused by a small group of neuromuscular disorders. This article reviews myotonia and its differential diagnosis. The use of electrodiagnostic testing to evaluate the primary myotonic disorders (myotonic dystrophy and the nondystrophic myotonias) is also discussed.

  11. Primary Hyperparathyroidism and Hyperthyroidism in a Patient with Myotonic Dystrophy: A Case Report and Review of the Literature.

    PubMed

    Cherif, Yosra; Zantour, Baha; Alaya, Wafa; Berriche, Olfa; Younes, Samia; Sfar, Mohamed Habib

    2015-01-01

    Various endocrine manifestations are commonly described in myotonic dystrophy (MD), including primary hypogonadism, diabetes mellitus, and thyroid and parathyroid dysfunction. We describe a 46-year-old woman with a family history of MD with her son. She was diagnosed with cardiac arrhythmia and required the implantation of a pacemaker. She was noted to have a bilateral cataract. She complained of muscle weakness, diffuse myalgia, and palpitation. The electromyography (EMG) showed myotonic discharges. Laboratory tests showed high serum calcium 2.83 mmol/L, serum phosphate 1.2 mmol/L, parathormone 362.5 pg/mL, thyroid stimulating hormone TSH 0.02 mIU/L (normal range: 0.34-5.6 mIU/L), FT4 21.17 ng/mL, and negative anti-thyroperoxidase antibodies. Cervical ultrasound revealed a multinodular goiter. The 99mTc-MIBI scintigraphy localized a lower right parathyroid adenoma. The clinical data, the family history of MD, EMG data, and endocrine disturbances were strongly suggestive of MD associated with hyperthyroidism and primary hyperparathyroidism. PMID:26175917

  12. Changes in pain-related beliefs, coping, and catastrophizing predict changes in pain intensity, pain interference, and psychological functioning in individuals with Myotonic Muscular Dystrophy and Facioscapulohumeral Dystrophy

    PubMed Central

    Nieto, Rubén; Raichle, Katherine A.; Jensen, Mark P.; Miró, Jordi

    2011-01-01

    Objectives The primary aim of this study was to test hypothesized associations between changes in psychological variables (i.e., pain beliefs, catastrophizing and coping strategies) and changes in pain intensity and related adjustment (i.e., pain interference and psychological functioning) in individuals with Myotonic Muscular Dystrophy (MMD) and Facioscapulohumeral Muscular Dystrophy (FSHD). Methods A sample of 107 adults with a diagnosis of MMD or FSHD, reporting pain in the past three months, completed assessments at two time-points, separated by about 24 months. Results Results showed that changes in pain-related psychological variables were significantly associated with changes in psychological functioning, pain intensity and pain interference. Specifically, increases in the belief that emotion influences pain, and catastrophizing were associated with decreases in psychological functioning. Increases in the coping strategies of asking for assistance and resting, and the increases of catastrophizing were associated with increases in pain intensity. Finally, increases in pain intensity and asking for assistance were associated with increases in pain interference. Discussion The results support the utility of the biopsychosocial model of pain for understanding pain and its impact in individuals with MMD or FSHD. These findings may inform the design and implementation of psychosocial pain treatments for people with muscular dystrophy and chronic pain. PMID:21642844

  13. Staufen1s role as a splicing factor and a disease modifier in Myotonic Dystrophy Type I

    PubMed Central

    Bondy-Chorney, Emma; Crawford Parks, Tara E.; Ravel-Chapuis, Aymeric; Jasmin, Bernard J.; Côté, Jocelyn

    2016-01-01

    ABSTRACT In a recent issue of PLOS Genetics, we reported that the double-stranded RNA-binding protein, Staufen1, functions as a disease modifier in the neuromuscular disorder Myotonic Dystrophy Type I (DM1). In this work, we demonstrated that Staufen1 regulates the alternative splicing of exon 11 of the human Insulin Receptor, a highly studied missplicing event in DM1, through Alu elements located in an intronic region. Furthermore, we found that Staufen1 overexpression regulates numerous alternative splicing events, potentially resulting in both positive and negative effects in DM1. Here, we discuss our major findings and speculate on the details of the mechanisms by which Staufen1 could regulate alternative splicing, in both normal and DM1 conditions. Finally, we highlight the importance of disease modifiers, such as Staufen1, in the DM1 pathology in order to understand the complex disease phenotype and for future development of new therapeutic strategies.

  14. Characterization and polymerase chain reaction (PCR) detection of an Alu deletion polymorphism in total linkage disequilibrium with myotonic dystrophy

    SciTech Connect

    Mahadevan, M.S. ); Foitzik, M.A. ); Surh, L.C.; Korneluk, R.G. Univ. of Ottawa )

    1993-02-01

    The mutation causing myotonic dystrophy has been identified as an unstable trinucleotide CRG repeat located in the 3[prime] untranslated region of a gene putatively encoding a serine-threonine protein kinase. The mutation has been reported to be in total linkage disequilibrium with an insertion/deletion polymorphism located within the kinase gene. To determine the nature of this polymorphism, we have sequenced this genomic fragment and have found that the sequence of this region consists of five consecutive Alu repeats. Further analysis suggests that the smaller of two alleles is actually due to a proposed deletion event that resulted in the loss of an equivalent of three Alu repeats. We have developed a PCR-based assay to detect this polymorphism, the closest, distal marker to the DM mutation. 12 refs., 2 figs.

  15. Staufen1s role as a splicing factor and a disease modifier in Myotonic Dystrophy Type I

    PubMed Central

    Bondy-Chorney, Emma; Crawford Parks, Tara E.; Ravel-Chapuis, Aymeric; Jasmin, Bernard J.; Côté, Jocelyn

    2016-01-01

    ABSTRACT In a recent issue of PLOS Genetics, we reported that the double-stranded RNA-binding protein, Staufen1, functions as a disease modifier in the neuromuscular disorder Myotonic Dystrophy Type I (DM1). In this work, we demonstrated that Staufen1 regulates the alternative splicing of exon 11 of the human Insulin Receptor, a highly studied missplicing event in DM1, through Alu elements located in an intronic region. Furthermore, we found that Staufen1 overexpression regulates numerous alternative splicing events, potentially resulting in both positive and negative effects in DM1. Here, we discuss our major findings and speculate on the details of the mechanisms by which Staufen1 could regulate alternative splicing, in both normal and DM1 conditions. Finally, we highlight the importance of disease modifiers, such as Staufen1, in the DM1 pathology in order to understand the complex disease phenotype and for future development of new therapeutic strategies. PMID:27695661

  16. Muscular Dystrophy

    MedlinePlus

    ... in Duchenne muscular dystrophy. Dev. Med. Child Neurol. Mar 1995;37(3):260-269. 4. Centers for ... DM1) . The International Myotonic Dystrophy Consortium (IDMC). Neurology. Mar 28 2000;54(6):1218-1221. 5. Harper ...

  17. Prenatal diagnosis of congenital myopathies and muscular dystrophies.

    PubMed

    Massalska, D; Zimowski, J G; Bijok, J; Kucińska-Chahwan, A; Łusakowska, A; Jakiel, G; Roszkowski, T

    2016-09-01

    Congenital myopathies and muscular dystrophies constitute a genetically and phenotypically heterogeneous group of rare inherited diseases characterized by muscle weakness and atrophy, motor delay and respiratory insufficiency. To date, curative care is not available for these diseases, which may severely affect both life-span and quality of life. We discuss prenatal diagnosis and genetic counseling for families at risk, as well as diagnostic possibilities in sporadic cases. PMID:27197572

  18. Gonosomal mosaicism in myotonic dystrophy patients: Involvement of mitotic events in (CTG)[sub n] repeat variation and selection against extreme expansion in sperm

    SciTech Connect

    Jansen, G.; Coerwinkel, M.; Wieringa, B.; Nillesen, W.; Smeets, H.; Brunner, H.; Wieringa, B. ); Willems, P.; Vits, L. ); Hoeweler, C. )

    1994-04-01

    Myotonic dystrophy (DM) is caused by abnormal expansion of a polymorphic (CTG)[sub n] repeat, located in the DM protein kinase gene. The authors determined the (CTG)[sub n] repeat lengths in a broad range of tissue DNAs from patients with mild, classical, or congenital manifestation of DM. Differences in the repeat length were seen in somatic tissues from single DM individuals and twins. Repeats appeared to expand to a similar extent in tissues originating from the same embryonal origin. In most male patients carrying intermediate- or small-sized expansions in blood, the repeat lengths covered a markedly wider range in sperm. In contrast, male patients with large allele expansions in blood (>700 CTGs) had similar or smaller repeats in sperm, when detectable. Sperm alleles with >1,000 CTGs were not seen. The authors conclude that DM patients can be considered gonosomal mosaics, i.e., combined somatic and germ-line tissue mosaics. Most remarkably, they observed multiple cases where the length distributions of intermediate- or small-sized alleles in fathers' sperm were significantly different from that in their offspring's blood. The combined findings indicate that intergenerational length changes in the unstable CTG repeat are most likely to occur during early embryonic mitotic divisions in both somatic and germ-line tissue formation. Both the initial CTG length, the overall number of cell divisions involved in tissue formation, and perhaps a specific selection process in spermatogenesis may influence the dynamics of this process. A model explaining mitotic instability and sex-dependent segregation phenomena in DM manifestation is discussed. 59 refs., 5 figs.

  19. Muscleblind-like 3 deficit results in a spectrum of age-associated pathologies observed in myotonic dystrophy

    PubMed Central

    Choi, Jongkyu; Dixon, Donald M.; Dansithong, Warunee; Abdallah, Walid F.; Roos, Kenneth P.; Jordan, Maria C.; Trac, Brandon; Lee, Han Shin; Comai, Lucio; Reddy, Sita

    2016-01-01

    Myotonic dystrophy type I (DM1) exhibits distinctive disease specific phenotypes and the accelerated onset of a spectrum of age-associated pathologies. In DM1, dominant effects of expanded CUG repeats result in part from the inactivation of the muscleblind-like (MBNL) proteins. To test the role of MBNL3, we deleted Mbnl3 exon 2 (Mbnl3ΔE2) in mice and examined the onset of age-associated diseases over 4 to 13 months of age. Accelerated onset of glucose intolerance with elevated insulin levels, cardiac systole deficits, left ventricle hypertrophy, a predictor of a later onset of heart failure and the development of subcapsular and cortical cataracts is observed in Mbnl3ΔE2 mice. Retention of embryonic splice isoforms in adult organs, a prominent defect in DM1, is not observed in multiple RNAs including the Insulin Receptor (Insr), Cardiac Troponin T (Tnnt2), Lim Domain Binding 3 (Ldb3) RNAs in Mbnl3ΔE2 mice. Although rare DM1-like splice errors underlying the observed phenotypes cannot be excluded, our data in conjunction with the reported absence of alternative splice errors in embryonic muscles of a similar Mbnl3ΔE2 mouse by RNA-seq studies, suggest that mechanisms distinct from the adult retention of embryonic splice patterns may make important contributions to the onset of age-associated pathologies in DM1. PMID:27484195

  20. Relationship between neuropsychological impairment and grey and white matter changes in adult-onset myotonic dystrophy type 1.

    PubMed

    Baldanzi, Sigrid; Cecchi, Paolo; Fabbri, Serena; Pesaresi, Ilaria; Simoncini, Costanza; Angelini, Corrado; Bonuccelli, Ubaldo; Cosottini, Mirco; Siciliano, Gabriele

    2016-01-01

    Myotonic dystrophy type 1 (DM1) has a wide phenotypic spectrum and potentially may affect central nervous system with mild to severe involvement. Our aim was to investigate grey matter (GM) and white matter (WM) structural alterations in a sample of adult-onset DM1 patients and to evaluate relationship with clinical and cognitive variables. Thirty DM1 patients underwent neuropsychological investigation and 3T-MRI protocol. GM and WM changes were evaluated calculating brain parenchymal fraction (BPF), voxel-based morphometry (VBM), white matter lesion load (LL% and Fazekas scale) and tract based spatial statistical (TBSS). Patients showed main impairment in tests exploring executive and mnesic domains with visuo-spatial involvement, significantly related to BPF. VBM revealed clusters of widespread GM reduction and TBSS revealed areas of decreased fractional anisotropy (FA) and increased radial diffusivity (RD), mean diffusivity (MD) and axial diffusivity (AD) in patients compared to a group of matched healthy controls. Multiple regression analyses showed areas of significant negative relationship between left temporal atrophy and verbal memory, between RD and mnesic and visuo-spatial cognitive domains, and between AD and verbal memory. TBSS results indicate that the involvement of normal appearance WM, beyond the signal changes detected with conventional MR imaging (Fazekas scale and LL%), was associated with neuropsychological deficit. These data suggest that disrupted complex neuronal networks can underlie cognitive-behavioural dysfunctions in DM1. PMID:27437180

  1. NMR spectroscopy and molecular dynamics simulation of r(CCGCUGCGG)₂ reveal a dynamic UU internal loop found in myotonic dystrophy type 1.

    PubMed

    Parkesh, Raman; Fountain, Matthew; Disney, Matthew D

    2011-02-01

    The NMR structure of an RNA with a copy of the 5'CUG/3'GUC motif found in the triplet repeating disorder myotonic dystrophy type 1 (DM1) is disclosed. The lowest energy conformation of the UU pair is a single-hydrogen bond structure; however, the UU protons undergo exchange indicating structural dynamics. Molecular dynamics simulations show that the single hydrogen bond structure is the most populated one but the UU pair interconverts among zero, one, and two hydrogen bond pairs. These studies have implications for the recognition of the DM1 RNA by small molecules and proteins.

  2. Quantifying Cancer Absolute Risk and Cancer Mortality in the Presence of Competing Events after a Myotonic Dystrophy Diagnosis

    PubMed Central

    Gadalla, Shahinaz M.; Pfeiffer, Ruth M.; Kristinsson, Sigurdur Y.; Björkholm, Magnus; Hilbert, James E.; Moxley, Richard T.; Landgren, Ola; Greene, Mark H.

    2013-01-01

    Recent studies show that patients with myotonic dystrophy (DM) have an increased risk of specific malignancies, but estimates of absolute cancer risk accounting for competing events are lacking. Using the Swedish Patient Registry, we identified 1,081 patients with an inpatient and/or outpatient diagnosis of DM between 1987 and 2007. Date and cause of death and date of cancer diagnosis were extracted from the Swedish Cause of Death and Cancer Registries. We calculated non-parametric estimates of absolute cancer risk and cancer mortality accounting for the high non-cancer competing mortality associated with DM. Absolute cancer risk after DM diagnosis was 1.6% (95% CI=0.4-4%), 5% (95% CI=3-9%) and 9% (95% CI=6-13%) at ages 40, 50 and 60 years, respectively. Females had a higher absolute risk of all cancers combined than males: 9% (95% CI=4-14), and 13% (95% CI=9-20) vs. 2% (95%CI= 0.7-6) and 4% (95%CI=2-8) by ages 50 and 60 years, respectively) and developed cancer at younger ages (median age =51 years, range=22-74 vs. 57, range=43-84, respectively, p=0.02). Cancer deaths accounted for 10% of all deaths, with an absolute cancer mortality risk of 2% (95%CI=1-4.5%), 4% (95%CI=2-6%), and 6% (95%CI=4-9%) by ages 50, 60, and 70 years, respectively. No gender difference in cancer-specific mortality was observed (p=0.6). In conclusion, cancer significantly contributes to morbidity and mortality in DM patients, even after accounting for high competing DM mortality from non-neoplastic causes. It is important to apply population-appropriate, validated cancer screening strategies in DM patients. PMID:24236163

  3. A low absolute number of expanded transcripts is involved in myotonic dystrophy type 1 manifestation in muscle

    PubMed Central

    Gudde, Anke E. E. G.; González-Barriga, Anchel; van den Broek, Walther J. A. A.; Wieringa, Bé; Wansink, Derick G.

    2016-01-01

    Muscular manifestation of myotonic dystrophy type 1 (DM1), a common inheritable degenerative multisystem disorder, is mainly caused by expression of RNA from a (CTG·CAG)n-expanded DM1 locus. Here, we report on comparative profiling of expression of normal and expanded endogenous or transgenic transcripts in skeletal muscle cells and biopsies from DM1 mouse models and patients in order to help us in understanding the role of this RNA-mediated toxicity. In tissue of HSALR mice, the most intensely used ‘muscle-only’ model in the DM1 field, RNA from the α-actin (CTG)250 transgene was at least 1000-fold more abundant than that from the Dmpk gene, or the DMPK gene in humans. Conversely, the DMPK transgene in another line, DM500/DMSXL mice, was expressed ∼10-fold lower than the endogenous gene. Temporal regulation of expanded RNA expression differed between models. Onset of expression occurred remarkably late in HSALR myoblasts during in vitro myogenesis whereas Dmpk or DMPK (trans)genes were expressed throughout proliferation and differentiation phases. Importantly, quantification of absolute transcript numbers revealed that normal and expanded Dmpk/DMPK transcripts in mouse models and DM1 patients are low-abundance RNA species. Northern blotting, reverse transcriptase–quantitative polymerase chain reaction, RNA-sequencing and fluorescent in situ hybridization analyses showed that they occur at an absolute number between one and a few dozen molecules per cell. Our findings refine the current RNA dominance theory for DM1 pathophysiology, as anomalous factor binding to expanded transcripts and formation of soluble or insoluble ribonucleoprotein aggregates must be nucleated by only few expanded DMPK transcripts and therefore be a small numbers game. PMID:26908607

  4. Intermolecular and Intramolecular Interactions Regulate Catalytic Activity of Myotonic Dystrophy Kinase-Related Cdc42-Binding Kinase α

    PubMed Central

    Tan, Ivan; Seow, Kah Tong; Lim, Louis; Leung, Thomas

    2001-01-01

    Myotonic dystrophy kinase-related Cdc42-binding kinase (MRCK) is a Cdc42-binding serine/threonine kinase with multiple functional domains. We had previously shown MRCKα to be implicated in Cdc42-mediated peripheral actin formation and neurite outgrowth in HeLa and PC12 cells, respectively. Here we demonstrate that native MRCK exists in high-molecular-weight complexes. We further show that the three independent coiled-coil (CC) domains and the N-terminal region preceding the kinase domain are responsible for intermolecular interactions leading to MRCKα multimerization. N terminus-mediated dimerization and consequent transautophosphorylation are critical processes regulating MRCKα catalytic activities. A region containing the two distal CC domains (CC2 and CC3; residues 658 to 930) was found to interact intramolecularly with the kinase domain and negatively regulates its activity. Its deletion also resulted in an active kinase, confirming a negative autoregulatory role. We provide evidence that the N terminus-mediated dimerization and activation of MRCK and the negative autoregulatory kinase–distal CC interaction are two mutually exclusive events that tightly regulate the catalytic state of the kinase. Disruption of this interaction by a mutant kinase domain resulted in increased kinase activity. MRCK kinase activity was also elevated when cells were treated with phorbol ester, which can interact directly with a cysteine-rich domain next to the distal CC domain. We therefore suggest that binding of phorbol ester to MRCK releases its autoinhibition, allowing N-terminal dimerization and subsequent kinase activation. PMID:11283256

  5. Relationship between muscle impairments, postural stability, and gait parameters assessed with lower-trunk accelerometry in myotonic dystrophy type 1.

    PubMed

    Bachasson, Damien; Moraux, Amélie; Ollivier, Gwenn; Decostre, Valérie; Ledoux, Isabelle; Gidaro, Teresa; Servais, Laurent; Behin, Anthony; Stojkovic, Tanya; Hébert, Luc J; Puymirat, Jack; Eymard, Bruno; Bassez, Guillaume; Hogrel, Jean-Yves

    2016-07-01

    This study evaluated gait using lower-trunk accelerometry and investigated relationships between gait abnormalities, postural instability, handgrip myotonia, and weakness in lower-limb and axial muscle groups commonly affected in myotonic dystrophy type 1 (DM1). Twenty-two patients (11 men, 11 women; age = 42 years (range: 26-51)) with DM1 and twenty healthy controls (9 men, 11 women; age = 44 years (range: 24-50)) participated in this study. Gait analysis using lower-trunk accelerometry was performed at self-selected walking pace. Postural stability was measured via center of pressure displacement analysis using a force platform during eyes-closed normal stance. Handgrip myotonia was quantified using force-relaxation curve modeling. Patients displayed lower walking speed, stride frequency, stride length, gait regularity, and gait symmetry. Strength of ankle plantar flexors, ankle dorsal flexors and neck flexors correlated with interstride regularity in the vertical direction (ρ = 0.57, ρ = 0.59, and ρ = 0.44, respectively; all P < 0.05). Knee extension strength correlated with gait symmetry in the anteroposterior direction (ρ = 0.45, P < 0.05). Center of pressure velocity was greater in patients and correlated with neck flexion and ankle plantar flexion weakness (ρ = -0.51 and ρ = -0.62, respectively; both P < 0.05), and with interstride regularity in the vertical direction (ρ = -0.58, P < 0.05). No correlation was found between handgrip myotonia and any other variable studied. Lower-trunk accelerometry allows the characterization of gait pattern abnormalities in patients with DM1. Further studies are required to determine the relevance of systematic gait analysis using lower-trunk accelerometry for patient follow-up and intervention planning. PMID:27234310

  6. A low absolute number of expanded transcripts is involved in myotonic dystrophy type 1 manifestation in muscle.

    PubMed

    Gudde, Anke E E G; González-Barriga, Anchel; van den Broek, Walther J A A; Wieringa, Bé; Wansink, Derick G

    2016-04-15

    Muscular manifestation of myotonic dystrophy type 1 (DM1), a common inheritable degenerative multisystem disorder, is mainly caused by expression of RNA from a (CTG·CAG)n-expanded DM1 locus. Here, we report on comparative profiling of expression of normal and expanded endogenous or transgenic transcripts in skeletal muscle cells and biopsies from DM1 mouse models and patients in order to help us in understanding the role of this RNA-mediated toxicity. In tissue of HSA(LR) mice, the most intensely used 'muscle-only' model in the DM1 field, RNA from the α-actin (CTG)250 transgene was at least 1000-fold more abundant than that from the Dmpk gene, or the DMPK gene in humans. Conversely, the DMPK transgene in another line, DM500/DMSXL mice, was expressed ∼10-fold lower than the endogenous gene. Temporal regulation of expanded RNA expression differed between models. Onset of expression occurred remarkably late in HSA(LR) myoblasts during in vitro myogenesis whereas Dmpk or DMPK (trans)genes were expressed throughout proliferation and differentiation phases. Importantly, quantification of absolute transcript numbers revealed that normal and expanded Dmpk/DMPK transcripts in mouse models and DM1 patients are low-abundance RNA species. Northern blotting, reverse transcriptase-quantitative polymerase chain reaction, RNA-sequencing and fluorescent in situ hybridization analyses showed that they occur at an absolute number between one and a few dozen molecules per cell. Our findings refine the current RNA dominance theory for DM1 pathophysiology, as anomalous factor binding to expanded transcripts and formation of soluble or insoluble ribonucleoprotein aggregates must be nucleated by only few expanded DMPK transcripts and therefore be a small numbers game. PMID:26908607

  7. Myotonic Dystrophy Type 1 RNA Crystal Structures Reveal Heterogeneous 1 × 1 Nucleotide UU Internal Loop Conformations

    SciTech Connect

    Kumar, Amit; Park, HaJeung; Fang, Pengfei; Parkesh, Raman; Guo, Min; Nettles, Kendall W.; Disney, Matthew D.

    2012-03-27

    RNA internal loops often display a variety of conformations in solution. Herein, we visualize conformational heterogeneity in the context of the 5'CUG/3'GUC repeat motif present in the RNA that causes myotonic dystrophy type 1 (DM1). Specifically, two crystal structures of a model DM1 triplet repeating construct, 5'r[{und UU}GGGC(C{und U}G){sub 3}GUCC]{sub 2}, refined to 2.20 and 1.52 {angstrom} resolution are disclosed. Here, differences in the orientation of the 5' dangling UU end between the two structures induce changes in the backbone groove width, which reveals that noncanonical 1 x 1 nucleotide UU internal loops can display an ensemble of pairing conformations. In the 2.20 {angstrom} structure, CUGa, the 5' UU forms a one hydrogen-bonded pair with a 5' UU of a neighboring helix in the unit cell to form a pseudoinfinite helix. The central 1 x 1 nucleotide UU internal loop has no hydrogen bonds, while the terminal 1 x 1 nucleotide UU internal loops each form a one-hydrogen bond pair. In the 1.52 {angstrom} structure, CUGb, the 5' UU dangling end is tucked into the major groove of the duplex. While the canonically paired bases show no change in base pairing, in CUGb the terminal 1 x 1 nucleotide UU internal loops now form two hydrogen-bonded pairs. Thus, the shift in the major groove induced by the 5' UU dangling end alters noncanonical base patterns. Collectively, these structures indicate that 1 x 1 nucleotide UU internal loops in DM1 may sample multiple conformations in vivo. This observation has implications for the recognition of this RNA, and other repeating transcripts, by protein and small molecule ligands.

  8. Myotonic dystrophy type 1 RNA crystal structures reveal heterogeneous 1 × 1 nucleotide UU internal loop conformations.

    PubMed

    Kumar, Amit; Park, HaJeung; Fang, Pengfei; Parkesh, Raman; Guo, Min; Nettles, Kendall W; Disney, Matthew D

    2011-11-15

    RNA internal loops often display a variety of conformations in solution. Herein, we visualize conformational heterogeneity in the context of the 5'CUG/3'GUC repeat motif present in the RNA that causes myotonic dystrophy type 1 (DM1). Specifically, two crystal structures of a model DM1 triplet repeating construct, 5'r[UUGGGC(CUG)(3)GUCC](2), refined to 2.20 and 1.52 Å resolution are disclosed. Here, differences in the orientation of the 5' dangling UU end between the two structures induce changes in the backbone groove width, which reveals that noncanonical 1 × 1 nucleotide UU internal loops can display an ensemble of pairing conformations. In the 2.20 Å structure, CUGa, the 5' UU forms a one hydrogen-bonded pair with a 5' UU of a neighboring helix in the unit cell to form a pseudoinfinite helix. The central 1 × 1 nucleotide UU internal loop has no hydrogen bonds, while the terminal 1 × 1 nucleotide UU internal loops each form a one-hydrogen bond pair. In the 1.52 Å structure, CUGb, the 5' UU dangling end is tucked into the major groove of the duplex. While the canonically paired bases show no change in base pairing, in CUGb the terminal 1 × 1 nucleotide UU internal loops now form two hydrogen-bonded pairs. Thus, the shift in the major groove induced by the 5' UU dangling end alters noncanonical base patterns. Collectively, these structures indicate that 1 × 1 nucleotide UU internal loops in DM1 may sample multiple conformations in vivo. This observation has implications for the recognition of this RNA, and other repeating transcripts, by protein and small molecule ligands.

  9. Detection of Slipped-DNAs at the Trinucleotide Repeats of the Myotonic Dystrophy Type I Disease Locus in Patient Tissues

    PubMed Central

    Axford, Michelle M.; Wang, Yuh-Hwa; Nakamori, Masayuki; Zannis-Hadjopoulos, Maria; Thornton, Charles A.; Pearson, Christopher E.

    2013-01-01

    Slipped-strand DNAs, formed by out-of-register mispairing of repeat units on complementary strands, were proposed over 55 years ago as transient intermediates in repeat length mutations, hypothesized to cause at least 40 neurodegenerative diseases. While slipped-DNAs have been characterized in vitro, evidence of slipped-DNAs at an endogenous locus in biologically relevant tissues, where instability varies widely, is lacking. Here, using an anti-DNA junction antibody and immunoprecipitation, we identify slipped-DNAs at the unstable trinucleotide repeats (CTG)n•(CAG)n of the myotonic dystrophy disease locus in patient brain, heart, muscle and other tissues, where the largest expansions arise in non-mitotic tissues such as cortex and heart, and are smallest in the cerebellum. Slipped-DNAs are shown to be present on the expanded allele and in chromatinized DNA. Slipped-DNAs are present as clusters of slip-outs along a DNA, with each slip-out having 1–100 extrahelical repeats. The allelic levels of slipped-DNA containing molecules were significantly greater in the heart over the cerebellum (relative to genomic equivalents of pre-IP input DNA) of a DM1 individual; an enrichment consistent with increased allelic levels of slipped-DNA structures in tissues having greater levels of CTG instability. Surprisingly, this supports the formation of slipped-DNAs as persistent mutation products of repeat instability, and not merely as transient mutagenic intermediates. These findings further our understanding of the processes of mutation and genetic variation. PMID:24367268

  10. Studying a Drug-like, RNA-Focused Small Molecule Library Identifies Compounds That Inhibit RNA Toxicity in Myotonic Dystrophy.

    PubMed

    Rzuczek, Suzanne G; Southern, Mark R; Disney, Matthew D

    2015-12-18

    There are many RNA targets in the transcriptome to which small molecule chemical probes and lead therapeutics are desired. However, identifying compounds that bind and modulate RNA function in cellulo is difficult. Although rational design approaches have been developed, they are still in their infancies and leave many RNAs "undruggable". In an effort to develop a small molecule library that is biased for binding RNA, we computationally identified "drug-like" compounds from screening collections that have favorable properties for binding RNA and for suitability as lead drugs. As proof-of-concept, this collection was screened for binding to and modulating the cellular dysfunction of the expanded repeating RNA (r(CUG)(exp)) that causes myotonic dystrophy type 1. Hit compounds bind the target in cellulo, as determined by the target identification approach Competitive Chemical Cross-Linking and Isolation by Pull-down (C-ChemCLIP), and selectively improve several disease-associated defects. The best compounds identified from our 320-member library are more potent in cellulo than compounds identified by high-throughput screening (HTS) campaigns against this RNA. Furthermore, the compound collection has a higher hit rate (9% compared to 0.01-3%), and the bioactive compounds identified are not charged; thus, RNA can be "drugged" with compounds that have favorable pharmacological properties. Finally, this RNA-focused small molecule library may serve as a useful starting point to identify lead "drug-like" chemical probes that affect the biological (dys)function of other RNA targets by direct target engagement.

  11. Motor unit reorganization in progressive muscular dystrophies and congenital myopathies.

    PubMed

    Szmidt-Sałkowska, Elżbieta; Gaweł, Małgorzata; Lipowska, Marta

    2015-01-01

    The aim of this study was to analyze motor unit reorganization in different types of progressive muscular dystrophies and congenital myopathies. The study population consisted of patients with genetically verified progressive muscular dystrophies: Duchenne (DMD) (n=54), Becker (BMD) (n=30), facio-scapulo-humeral (FSHD) (n=37), and Emery-Dreifuss (E-DD) (n=26). Patients with probable limb-girdle dystrophy (L-GD) (n=58) and congenital myopathies (n=35) were also included in the study. Quantitative EMG recordings were obtained from 469 muscles. Muscle activity at rest and during slight voluntary and maximal muscle contraction was analyzed. The motor unit activity potential (MUAP) duration, amplitude, area, size index (SI), polyphasicity, and the presence of "outliers" were evaluated. Diminished values of MUAP parameters and decreased maximal amplitude of maximal muscle contraction were recorded most frequently in DMD and mainly in the biceps brachii muscles. SI was the most frequently changed EMG parameter. "Outliers" with amplitude below the normal range were recorded more frequently then a decreased mean MUAP amplitude (what could indicate a very high sensitivity of this EMG parameter). Pathological interference pattern was recorded in 34.7% of biceps brachii and in 21.2% of rectus femoris muscles. In FSHD, decreased MUAP duration and SI and pathological interference pattern with low amplitude were recorded most frequently in the tibial anterior and deltoid muscles. The presence of potentials with reduced parameters is a result of decreasing motor unit area (reduced number and size of muscle fibers), while high amplitude potentials recorded in BMD and E-DD could indicate a slow and mild course of disease and muscle regeneration.

  12. Motor unit reorganization in progressive muscular dystrophies and congenital myopathies.

    PubMed

    Szmidt-Sałkowska, Elżbieta; Gaweł, Małgorzata; Lipowska, Marta

    2015-01-01

    The aim of this study was to analyze motor unit reorganization in different types of progressive muscular dystrophies and congenital myopathies. The study population consisted of patients with genetically verified progressive muscular dystrophies: Duchenne (DMD) (n=54), Becker (BMD) (n=30), facio-scapulo-humeral (FSHD) (n=37), and Emery-Dreifuss (E-DD) (n=26). Patients with probable limb-girdle dystrophy (L-GD) (n=58) and congenital myopathies (n=35) were also included in the study. Quantitative EMG recordings were obtained from 469 muscles. Muscle activity at rest and during slight voluntary and maximal muscle contraction was analyzed. The motor unit activity potential (MUAP) duration, amplitude, area, size index (SI), polyphasicity, and the presence of "outliers" were evaluated. Diminished values of MUAP parameters and decreased maximal amplitude of maximal muscle contraction were recorded most frequently in DMD and mainly in the biceps brachii muscles. SI was the most frequently changed EMG parameter. "Outliers" with amplitude below the normal range were recorded more frequently then a decreased mean MUAP amplitude (what could indicate a very high sensitivity of this EMG parameter). Pathological interference pattern was recorded in 34.7% of biceps brachii and in 21.2% of rectus femoris muscles. In FSHD, decreased MUAP duration and SI and pathological interference pattern with low amplitude were recorded most frequently in the tibial anterior and deltoid muscles. The presence of potentials with reduced parameters is a result of decreasing motor unit area (reduced number and size of muscle fibers), while high amplitude potentials recorded in BMD and E-DD could indicate a slow and mild course of disease and muscle regeneration. PMID:26188938

  13. Treatment of sleep central apnea with non-invasive mechanical ventilation with 2 levels of positive pressure (bilevel) in a patient with myotonic dystrophy type 1

    PubMed Central

    Akamine, Ricardo Tera; Grossklauss, Luís Fernando; Moreira, Gustavo Antonio; Pradella-Hallinan, Marcia; Chiéia, Marco Antônio; Mesquita, Denis; Bulle Oliveira, Acary Souza; Tufik, Sergio

    2014-01-01

    We are reporting a case of a 29 year-old female with diagnosis of myotonic dystrophy type 1 (Steinert’s disease) with excessive daytime sleepiness, muscle fatigue, snoring, frequent arousals, non-restorative sleep, and witnessed apneas. Pulmonary function tests revealed a mild decrease of forced vital capacity. Nocturnal polysomnography showed an increase of apnea/hypopnea index (85.9 events/h), mainly of central type (236), minimal oxygen saturation of 72%, and end-tidal carbon dioxide values that varied from 45 to 53 mmHg. Bi-level positive airway pressure titration was initiated at an inspiratory pressure (IPAP) of 8 and an expiratory pressure (EPAP) of 4 cm H2O. IPAP was then gradually increased to eliminate respiratory events and improve oxygen saturation. An IPAP of 12cm H20 and an EPAP of 4cm H2O eliminated all respiratory events, and the oxygen saturation remained above 90%. Bi-level positive airway pressure treatment at spontaneous/timed mode showed an improvement in snoring, apneas, and Epworth sleepiness scale decreased from 20 to 10. This case illustrates the beneficial effects of Bi-level positive airway pressure support in central sleep apnea syndrome of a patient with myotonic dystrophy type 1. PMID:26483914

  14. Tendon Extracellular Matrix Alterations in Ullrich Congenital Muscular Dystrophy

    PubMed Central

    Sardone, Francesca; Traina, Francesco; Bondi, Alice; Merlini, Luciano; Santi, Spartaco; Maraldi, Nadir Mario; Faldini, Cesare; Sabatelli, Patrizia

    2016-01-01

    Collagen VI (COLVI) is a non-fibrillar collagen expressed in skeletal muscle and most connective tissues. Mutations in COLVI genes cause two major clinical forms, Bethlem myopathy and Ullrich congenital muscular dystrophy (UCMD). In addition to congenital muscle weakness, patients affected by COLVI myopathies show axial and proximal joint contractures and distal joint hypermobility, which suggest the involvement of the tendon function. We examined a peroneal tendon biopsy and tenocyte culture of a 15-year-old patient affected by UCMD with compound heterozygous COL6A2 mutations. In patient’s tendon biopsy, we found striking morphological alterations of tendon fibrils, consisting in irregular profiles and reduced mean diameter. The organization of the pericellular matrix of tenocytes, the primary site of collagen fibril assembly, was severely affected, as determined by immunoelectron microscopy, which showed an abnormal accumulation of COLVI and altered distribution of collagen I (COLI) and fibronectin (FBN). In patient’s tenocyte culture, COLVI web formation and cell surface association were severely impaired; large aggregates of COLVI, which matched with COLI labeling, were frequently detected in the extracellular matrix. In addition, metalloproteinase MMP-2, an extracellular matrix-regulating enzyme, was increased in the conditioned medium of patient’s tenocytes, as determined by gelatin zymography and western blot. Altogether, these data indicate that COLVI deficiency may influence the organization of UCMD tendon matrix, resulting in dysfunctional fibrillogenesis. The alterations of tendon matrix may contribute to the complex pathogenesis of COLVI related myopathies. PMID:27375477

  15. Tendon Extracellular Matrix Alterations in Ullrich Congenital Muscular Dystrophy.

    PubMed

    Sardone, Francesca; Traina, Francesco; Bondi, Alice; Merlini, Luciano; Santi, Spartaco; Maraldi, Nadir Mario; Faldini, Cesare; Sabatelli, Patrizia

    2016-01-01

    Collagen VI (COLVI) is a non-fibrillar collagen expressed in skeletal muscle and most connective tissues. Mutations in COLVI genes cause two major clinical forms, Bethlem myopathy and Ullrich congenital muscular dystrophy (UCMD). In addition to congenital muscle weakness, patients affected by COLVI myopathies show axial and proximal joint contractures and distal joint hypermobility, which suggest the involvement of the tendon function. We examined a peroneal tendon biopsy and tenocyte culture of a 15-year-old patient affected by UCMD with compound heterozygous COL6A2 mutations. In patient's tendon biopsy, we found striking morphological alterations of tendon fibrils, consisting in irregular profiles and reduced mean diameter. The organization of the pericellular matrix of tenocytes, the primary site of collagen fibril assembly, was severely affected, as determined by immunoelectron microscopy, which showed an abnormal accumulation of COLVI and altered distribution of collagen I (COLI) and fibronectin (FBN). In patient's tenocyte culture, COLVI web formation and cell surface association were severely impaired; large aggregates of COLVI, which matched with COLI labeling, were frequently detected in the extracellular matrix. In addition, metalloproteinase MMP-2, an extracellular matrix-regulating enzyme, was increased in the conditioned medium of patient's tenocytes, as determined by gelatin zymography and western blot. Altogether, these data indicate that COLVI deficiency may influence the organization of UCMD tendon matrix, resulting in dysfunctional fibrillogenesis. The alterations of tendon matrix may contribute to the complex pathogenesis of COLVI related myopathies. PMID:27375477

  16. Myotonic disorders: A review article

    PubMed Central

    Hahn, Chris; Salajegheh, Mohammad Kian

    2016-01-01

    The myotonic disorders are a heterogeneous group of genetically determined diseases that are unified by the presence of myotonia, which is defined as failure of muscle relaxation after activation. The presentation of these disorders can range from asymptomatic electrical myotonia, as seen in some forms of myotonia congenita (MC), to severe disability with muscle weakness, cardiac conduction defects, and other systemic features as in myotonic dystrophy type I (DM1). In this review, we describe the clinical features and pathophysiology of the different myotonic disorders, their laboratory and electrophysiologic findings and briefly review the currently available treatments. PMID:27141276

  17. Learning about Myotonic Dystrophy

    MedlinePlus

    ... for Patient Care Education All About the Human Genome Project Fact Sheets Genetic Education Resources for Teachers ... Education Kit Online Genetics Education Resources Smithsonian NHGRI Genome Exhibition Talking Glossary: English Talking Glossary: Español Issues ...

  18. Efficient and highly sensitive screen for myotonic dystrophy type 1 using a one-step triplet-primed PCR and melting curve assay.

    PubMed

    Lian, Mulias; Rajan-Babu, Indhu-Shree; Singh, Kunal; Lee, Caroline G; Law, Hai-Yang; Chong, Samuel S

    2015-03-01

    Instability and expansion of the DMPK CTG repeat cause myotonic dystrophy type 1 (DM1), the most common adult-onset neuromuscular disorder. Overlapping clinical features between DM1 and other myotonic disorders necessitate molecular confirmation for definitive diagnosis. Preconception screening could improve reproductive planning especially in DM1-affected women, who show diminished ovarian reserve and unfavorable in vitro fertilization-preimplantation genetic diagnosis outcome. We optimized triplet-primed PCR and melting curve analysis on 17 DNAs from DM1-affected/unaffected cell lines. A blinded test was performed on 60 genotype-known clinical samples. Plasmid constructs pDMPK(CTG)35 and pDMPK(CTG)48 were used to establish threshold temperatures separating DM1-affected from unaffected samples. Postscreen triplet-primed PCR amplicon sizing was achieved by short-cycle labeled-primer extension followed by capillary electrophoresis. Triplet-primed PCR melting curve analysis melt peak temperatures of unaffected and DM1-affected samples were lower and higher than the control plasmids' melt peak temperatures, respectively. Capillary electrophoresis of post-melting curve analysis amplicons was completely concordant with the screening results. Triplet-primed PCR melting curve analysis is a simple and cost-effective screening tool for rapid identification of DM1. The companion confirmation protocol allows quick determination of CTG repeat size when required. This strategy avoids the need to perform capillary electrophoresis sizing on all test samples, limiting capillary electrophoresis analysis to only a subset of cases that are screen-positive. PMID:25684273

  19. Haplotype-phenotype correlation in Fukuyama congenital muscular dystrophy.

    PubMed

    Saito, K; Osawa, M; Wang, Z P; Ikeya, K; Fukuyama, Y; Kondo-Iida, E; Toda, T; Ohashi, H; Kurosawa, K; Wakai, S; Kaneko, K

    2000-05-29

    In typical Fukuyama congenital muscular dystrophy (FCMD), peak motor function is usually only unassisted sitting or sliding on the buttocks, though a few patients are able to walk at some point. However, a few patients have a severe phenotype and never acquire head control. In addition, it is clinically difficult to differentiate this severe FCMD from Walker-Warburg syndrome (WWS) or from muscle-eye-brain disease (MEBD). In order to establish a genotype-phenotype correlation, we performed haplotype analysis using microsatellite markers closest to the FCMD gene (FCMD) in 56 Japanese FCMD families, including 35 families whose children were diagnosed as FCMD with the typical phenotype, 12 families with a mild phenotype, and 9 families with a severe phenotype. Of the 12 propositi with the mild phenotype, 8 could walk and the other 4 could stand with support; 10 cases were homozygous for the ancestral founder (A-F) haplotype whereas the other 2 were heterozygous for the haplotype. In the 9 severe cases, who had never acquired head control or the ability to sit without support, 3 had progressive hydrocephalus, 2 required a shunt operation, and 7 had ophthalmological abnormalities. Haplotype analysis showed that 8 of the 9 cases of the severe phenotype are heterozygous for the A-F haplotype, and the other one homozygous for the haplotype. We confirmed that at least one chromosome in each of the 56 FCMD patients has the A-F haplotype. The rate of heterozygosity for the A-F haplotypes was significantly higher in severe cases than in typical or mild cases (P < 0.005). Severe FCMD patients appeared to be compound heterozygotes for the founder mutation and another mutation. Thus, the present study yielded molecular genetic evidence of a broad clinical spectrum in FCMD.

  20. Cerebro-oculo-muscular syndrome: a variant of Fukuyama congenital cerebromuscular dystrophy.

    PubMed

    Dambska, M; Wisniewski, K; Sher, J; Solish, G

    1982-01-01

    Familial occurrence of cerebral malformations with muscular dystrophy was described by Fukuyama as congenital cerebromuscular dystrophy. We have observed a new syndrome belonging to the same group in three siblings. These syndromes differ in the degree of CNS involvement and abnormalities in the eye. The main clinical characteristics of our cohort were dysmorphic face, hypotonia, areflexia, failure to thrive, corneal opacity, cataract, dysgenesis of the anterior chamber of the eye, and death within the 1st year of life. Hydrocephalus and agyria were verified by computed tomography. Neuropathologic examination demonstrated malformations of the CNS. The agyric hemispheres with polymicrogyria in several cortical segments and severe cortical disorganization in other segments represented the principal anomaly. Congenital muscular dystrophy was also found. The CNS anomalies demonstrated a long-lasting pathologic process extending to involve the eye and muscle, which is most likely an inborn error of metabolism with autosomal recessive inheritance.

  1. [Genetic Variability and Structure of SNP Haplotypes in the DMPK Gene in Yakuts and Other Ethnic Groups of Northern Eurasia in Relation to Myotonic Dystrophy].

    PubMed

    Swarovskaya, M G; Stepanova, S K; Marussin, A V; Sukhomyasova, A L; Maximova, N R; Stepanov, V A

    2015-06-01

    The genetic variability of the DMPK locus has been studied in relation to six SNP markers (rs2070736, rs572634, rs1799894, rs527221, rs915915, and rs10415988) in Yakuts with myotonic dystrophy (MD) in the Yakut population and in populations of northern Eurasia. Significant differences were observed in the allele frequencies between patients and a population sample of Yakuts for three SNP loci (rs915915, rs1799894, and rs10415988) associated with a high chance of disease manifestation. The odds ratios (OR) of MD development in representatives of the Yakut population for these three loci were 2.59 (95% CI, p = 0,004), 4.99 (95% CI, p = 0.000), and 3.15 (95% CI, p = 0.01), respectively. Haplotype TTTCTC, which is associated with MD, and haplotype GTCCTT, which was observed only in Yakut MD patients (never in MD patients of non-Yakut origin), were revealed. A low level of variability in the locus of DMRK gene in Yakuts (H(e) = 0.283) compared with other examined populations was noted. An analysis of pairwise genetic relationships between populations revealed their significant differentiation for all the examined loci. In addition, a low level of differentiation in territorial groups of Yakut populations (F(ST) = 0.79%), which was related to the high subdivision of the northern Eurasian population (F(ST) = 11.83%), was observed. PMID:26310035

  2. Myotonic dystrophy kinase-related Cdc42-binding kinases (MRCK), the ROCK-like effectors of Cdc42 and Rac1

    PubMed Central

    Zhao, Zhuoshen; Manser, Ed

    2015-01-01

    Cdc42 is a member of the Rho GTPase protein family that plays key roles in local F-actin organization through a number of kinase and non-kinase effector proteins. The myotonic dystrophy kinase-related Cdc42-binding kinases (MRCKs), and the RhoA binding coiled-coil containing kinases (ROCKs) are widely expressed members of the Dystrophia myotonica protein kinase (DMPK) family. The MRCK proteins are ∼190 kDa multi-domain proteins expressed in all cells and coordinate certain acto-myosin networks. Notably MRCK is a key regulator of myosin18A and myosin IIA/B, and through phosphorylation of their common regulatory light chains (MYL9 or MLC2) to promote actin stress fiber contractility. The MRCK kinases are regulated by Cdc42, which is required for cell polarity and directional migration; MRCK links to the acto-myosin complex through interaction with a coiled-coil containing adaptor proteins LRAP35a/b. The biological activities of MRCK in model organisms such as worms and flies confirm it as a myosin II activator. In mammalian cell culture MRCK can be critical for cancer cell migration and neurite outgrowth. We review the current literatures regarding MRCK and highlight the similarities and differences between MRCK and ROCK kinases. PMID:26090570

  3. From dynamic combinatorial 'hit' to lead: in vitro and in vivo activity of compounds targeting the pathogenic RNAs that cause myotonic dystrophy.

    PubMed

    Ofori, Leslie O; Hoskins, Jason; Nakamori, Masayuki; Thornton, Charles A; Miller, Benjamin L

    2012-07-01

    The myotonic dystrophies (DM) are human diseases in which the accumulation of toxic RNA (CUG or CCUG) repeats in the cell causes sequestration of splicing factors, including MBNL1, leading to clinical symptoms such as muscle wasting and myotonia. We previously used Dynamic Combinatorial Chemistry to identify the first compounds known to inhibit (CUG)-MBNL1 binding in vitro. We now report transformation of those compounds into structures with activity in vivo. Introduction of a benzo[g]quinoline substructure previously unknown in the context of RNA recognition, as well as other modifications, provided several molecules with enhanced binding properties, including compounds with strong selectivity for CUG repeats over CAG repeats or CAG-CUG duplex RNA. Compounds readily penetrate cells, and improve luciferase activity in a mouse myoblast assay in which enzyme function is coupled to a release of nuclear CUG-RNA retention. Most importantly, two compounds are able to partially restore splicing in a mouse model of DM1. PMID:22492623

  4. Uncovering the Role of Hypermethylation by CTG Expansion in Myotonic Dystrophy Type 1 Using Mutant Human Embryonic Stem Cells

    PubMed Central

    Yanovsky-Dagan, Shira; Avitzour, Michal; Altarescu, Gheona; Renbaum, Paul; Eldar-Geva, Talia; Schonberger, Oshrat; Mitrani-Rosenbaum, Stella; Levy-Lahad, Ephrat; Birnbaum, Ramon Y.; Gepstein, Lior; Epsztejn-Litman, Silvina; Eiges, Rachel

    2015-01-01

    Summary CTG repeat expansion in DMPK, the cause of myotonic dystrophy type 1 (DM1), frequently results in hypermethylation and reduced SIX5 expression. The contribution of hypermethylation to disease pathogenesis and the precise mechanism by which SIX5 expression is reduced are unknown. Using 14 different DM1-affected human embryonic stem cell (hESC) lines, we characterized a differentially methylated region (DMR) near the CTGs. This DMR undergoes hypermethylation as a function of expansion size in a way that is specific to undifferentiated cells and is associated with reduced SIX5 expression. Using functional assays, we provide evidence for regulatory activity of the DMR, which is lost by hypermethylation and may contribute to DM1 pathogenesis by causing SIX5 haplo-insufficiency. This study highlights the power of hESCs in disease modeling and describes a DMR that functions both as an exon coding sequence and as a regulatory element whose activity is epigenetically hampered by a heritable mutation. PMID:26190529

  5. The small GTP-binding protein Rho binds to and activates a 160 kDa Ser/Thr protein kinase homologous to myotonic dystrophy kinase.

    PubMed Central

    Ishizaki, T; Maekawa, M; Fujisawa, K; Okawa, K; Iwamatsu, A; Fujita, A; Watanabe, N; Saito, Y; Kakizuka, A; Morii, N; Narumiya, S

    1996-01-01

    The small GTP-binding protein Rho functions as a molecular switch in the formation of focal adhesions and stress fibers, cytokinesis and transcriptional activation. The biochemical mechanism underlying these actions remains unknown. Using a ligand overlay assay, we purified a 160 kDa platelet protein that bound specifically to GTP-bound Rho. This protein, p160, underwent autophosphorylation at its serine and threonine residues and showed the kinase activity to exogenous substrates. Both activities were enhanced by the addition of GTP-bound Rho. A cDNA encoding p160 coded for a 1354 amino acid protein. This protein has a Ser/Thr kinase domain in its N-terminus, followed by a coiled-coil structure approximately 600 amino acids long, and a cysteine-rich zinc finger-like motif and a pleckstrin homology region in the C-terminus. The N-terminus region including a kinase domain and a part of coiled-coil structure showed strong homology to myotonic dystrophy kinase over 500 residues. When co-expressed with RhoA in COS cells, p160 was co-precipitated with the expressed Rho and its kinase activity was activated, indicating that p160 can associate physically and functionally with Rho both in vitro and in vivo. Images PMID:8617235

  6. Phenylbutazone induces expression of MBNL1 and suppresses formation of MBNL1-CUG RNA foci in a mouse model of myotonic dystrophy

    PubMed Central

    Chen, Guiying; Masuda, Akio; Konishi, Hiroyuki; Ohkawara, Bisei; Ito, Mikako; Kinoshita, Masanobu; Kiyama, Hiroshi; Matsuura, Tohru; Ohno, Kinji

    2016-01-01

    Myotonic dystrophy type 1 (DM1) is caused by abnormal expansion of CTG repeats in the 3′ untranslated region of the DMPK gene. Expanded CTG repeats are transcribed into RNA and make an aggregate with a splicing regulator, MBNL1, in the nucleus, which is called the nuclear foci. The nuclear foci sequestrates and downregulates availability of MBNL1. Symptomatic treatments are available for DM1, but no rational therapy is available. In this study, we found that a nonsteroidal anti-inflammatory drug (NSAID), phenylbutazone (PBZ), upregulated the expression of MBNL1 in C2C12 myoblasts as well as in the HSALR mouse model for DM1. In the DM1 mice model, PBZ ameliorated aberrant splicing of Clcn1, Nfix, and Rpn2. PBZ increased expression of skeletal muscle chloride channel, decreased abnormal central nuclei of muscle fibers, and improved wheel-running activity in HSALR mice. We found that the effect of PBZ was conferred by two distinct mechanisms. First, PBZ suppressed methylation of an enhancer region in Mbnl1 intron 1, and enhanced transcription of Mbnl1 mRNA. Second, PBZ attenuated binding of MBNL1 to abnormally expanded CUG repeats in cellulo and in vitro. Our studies suggest that PBZ is a potent therapeutic agent for DM1 that upregulates availability of MBNL1. PMID:27126921

  7. Recessive ACTA1 variant causes congenital muscular dystrophy with rigid spine.

    PubMed

    O'Grady, Gina L; Best, Heather A; Oates, Emily C; Kaur, Simranpreet; Charlton, Amanda; Brammah, Susan; Punetha, Jaya; Kesari, Akanchha; North, Kathryn N; Ilkovski, Biljana; Hoffman, Eric P; Clarke, Nigel F

    2015-06-01

    Variants in ACTA1, which encodes α-skeletal actin, cause several congenital myopathies, most commonly nemaline myopathy. Autosomal recessive variants comprise approximately 10% of ACTA1 myopathy. All recessive variants reported to date have resulted in loss of skeletal α-actin expression from muscle and severe weakness from birth. Targeted next-generation sequencing in two brothers with congenital muscular dystrophy with rigid spine revealed homozygous missense variants in ACTA1. Skeletal α-actin expression was preserved in these patients. This report expands the clinical and histological phenotype of ACTA1 disease to include congenital muscular dystrophy with rigid spine and dystrophic features on muscle biopsy. This represents a new class of recessive ACTA1 variants, which do not abolish protein expression. PMID:25182138

  8. Congenital muscular dystrophy with glycosylation defects of alpha-dystroglycan in Japan.

    PubMed

    Matsumoto, Hiroshi; Hayashi, Yukiko K; Kim, Dae-Son; Ogawa, Megumu; Murakami, Terumi; Noguchi, Satoru; Nonaka, Ikuya; Nakazawa, Tomoyuki; Matsuo, Takiko; Futagami, Satoshi; Campbell, Kevin P; Nishino, Ichizo

    2005-05-01

    Glycosylation defects of alpha-dystroglycan (alpha-DG) cause various muscular dystrophies. We performed clinical, pathological and genetic analyses of 62 Japanese patients with congenital muscular dystrophy, whose skeletal muscle showed deficiency of glycosylated form of alpha-DG. We found, the first Japanese patient with congenital muscular dystrophy 1C with a novel compound heterozygous mutation in the fukutin-related protein gene. Fukuyama-type congenital muscular dystrophy was genetically confirmed in 54 of 62 patients. Two patients with muscle-eye-brain disease and one Walker-Warburg syndrome were also genetically confirmed. Four patients had no mutation in any known genes associated with glycosylation of alpha-DG. Interestingly, the molecular mass of alpha-DG in the skeletal muscle was similar and was reduced to approximately 90 kDa among these patients, even though the causative gene and the clinico-pathological severity were different. This result suggests that other factors can modify clinical features of the patients with glycosylation defects of alpha-DG. PMID:15833426

  9. If you build a rare disease registry, will they enroll and will they use it? Methods and data from the National Registry of Myotonic Dystrophy (DM) and Facioscapulohumeral Muscular Dystrophy (FSHD)

    PubMed Central

    Hilbert, James E.; Kissel, John T.; Luebbe, Elizabeth A.; Martens, William B.; McDermott, Michael P.; Sanders, Donald B.; Tawil, Rabi; Thornton, Charles A.; Moxley, Richard T.

    2011-01-01

    Introduction Registries are becoming increasingly important for rare diseases as experimental therapies develop. This report describes the methodology behind the National Registry of Myotonic Dystrophy (DM) and Facioscapulohumeral Muscular Dystrophy (FSHD) Patients and Family Members to facilitate the development of other rare disease registries. We also highlight data about the pathophysiology and select burdens of DM and FSHD reported at baseline and longitudinally. Methods The Registry consists of de-identified, patient reported information collected at baseline and annually and information from review of medical records. Investigators can use the Registry to analyze de-identified data and to facilitate recruitment into clinical studies. Results To date, the Registry has enrolled 1611 members, facilitated 24 studies, and collected data annually for up to 8 years. Genetic test results were obtained in 56.2% of enrollees. Approximately one-third of members used assistive devices and another one-third reported psychological problems at baseline. Wheelchair use was reported for both short and long distances by 7.0% of DM and 18.1% of FSHD members. Approximately 60% of members reported their employment was affected by their disease. Conclusions Strengths of the Registry include large sample sizes, stringent review of clinical and molecular data, annually updated information, and regular interactions between patients and investigators. Registry data provide new insights into the burdens of DM and FSHD, such as, psychological problems and reduced employment. Opportunities abound for investigators to utilize Registry resources to assess the impact of these and other burdens on health care costs, progression of symptoms, and quality of life. PMID:22155025

  10. Gender as a Modifying Factor Influencing Myotonic Dystrophy Type 1 Phenotype Severity and Mortality: A Nationwide Multiple Databases Cross-Sectional Observational Study

    PubMed Central

    Hamroun, Dalil; Varet, Hugo; Fabbro, Marianne; Rougier, Felix; Amarof, Khadija; Arne Bes, Marie-Christine; Bedat-Millet, Anne-Laure; Behin, Anthony; Bellance, Remi; Bouhour, Françoise; Boutte, Celia; Boyer, François; Campana-Salort, Emmanuelle; Chapon, Françoise; Cintas, Pascal; Desnuelle, Claude; Deschamps, Romain; Drouin-Garraud, Valerie; Ferrer, Xavier; Gervais-Bernard, Helene; Ghorab, Karima; Laforet, Pascal; Magot, Armelle; Magy, Laurent; Menard, Dominique; Minot, Marie-Christine; Nadaj-Pakleza, Aleksandra; Pellieux, Sybille; Pereon, Yann; Preudhomme, Marguerite; Pouget, Jean; Sacconi, Sabrina; Sole, Guilhem; Stojkovich, Tanya; Tiffreau, Vincent; Urtizberea, Andoni; Vial, Christophe; Zagnoli, Fabien; Caranhac, Gilbert; Bourlier, Claude; Riviere, Gerard; Geille, Alain; Gherardi, Romain K.; Eymard, Bruno; Puymirat, Jack; Katsahian, Sandrine; Bassez, Guillaume

    2016-01-01

    Background Myotonic Dystrophy type 1 (DM1) is one of the most heterogeneous hereditary disease in terms of age of onset, clinical manifestations, and severity, challenging both medical management and clinical trials. The CTG expansion size is the main factor determining the age of onset although no factor can finely predict phenotype and prognosis. Differences between males and females have not been specifically reported. Our aim is to study gender impact on DM1 phenotype and severity. Methods We first performed cross-sectional analysis of main multiorgan clinical parameters in 1409 adult DM1 patients (>18y) from the DM-Scope nationwide registry and observed different patterns in males and females. Then, we assessed gender impact on social and economic domains using the AFM-Téléthon DM1 survey (n = 970), and morbidity and mortality using the French National Health Service Database (n = 3301). Results Men more frequently had (1) severe muscular disability with marked myotonia, muscle weakness, cardiac, and respiratory involvement; (2) developmental abnormalities with facial dysmorphism and cognitive impairment inferred from low educational levels and work in specialized environments; and (3) lonely life. Alternatively, women more frequently had cataracts, dysphagia, digestive tract dysfunction, incontinence, thyroid disorder and obesity. Most differences were out of proportion to those observed in the general population. Compared to women, males were more affected in their social and economic life. In addition, they were more frequently hospitalized for cardiac problems, and had a higher mortality rate. Conclusion Gender is a previously unrecognized factor influencing DM1 clinical profile and severity of the disease, with worse socio-economic consequences of the disease and higher morbidity and mortality in males. Gender should be considered in the design of both stratified medical management and clinical trials. PMID:26849574

  11. A novel recessive GUCY2D mutation causing cone-rod dystrophy and not Leber's congenital amaurosis.

    PubMed

    Ugur Iseri, Sibel A; Durlu, Yusuf K; Tolun, Aslihan

    2010-10-01

    Cone-rod dystrophies are inherited retinal dystrophies that are characterized by progressive degeneration of cones and rods, causing an early decrease in central visual acuity and colour vision defects, followed by loss of peripheral vision in adolescence or early adult life. Both genetic and clinical heterogeneity are well known. In a family with autosomal recessive cone-rod dystrophy, genetic analyses comprising genome scan with microsatellite markers, fine mapping and candidate gene approach resulted in the identification of a homozygous missense GUCY2D mutation. This is the first GUCY2D mutation associated with autosomal recessive cone-rod dystrophy rather than Leber's congenital amaurosis (LCA), a severe disease leading to childhood blindness. This study hence establishes GUCY2D, which is a common cause for both recessive LCA and dominant cone-rod dystrophy, as a good candidate for autosomal recessive cone-rod dystrophy. PMID:20517349

  12. Cortical and Subcortical Grey and White Matter Atrophy in Myotonic Dystrophies Type 1 and 2 Is Associated with Cognitive Impairment, Depression and Daytime Sleepiness

    PubMed Central

    Prehn, Christian; Krogias, Christos; Schneider, Ruth; Klein, Jan; Gold, Ralf; Lukas, Carsten

    2015-01-01

    Objectives Central nervous system involvement is one important clinical aspect of myotonic dystrophy type 1 and 2 (DM1 and DM2). We assessed CNS involvement DM1 and DM2 by 3T MRI and correlated clinical and neuocognitive symptoms with brain volumetry and voxel-based morphometry (VBM). Methods 12 patients with juvenile or classical DM1 and 16 adult DM2 patients underwent 3T MRI, a thorough neurological and neuropsychological examination and scoring of depression and daytime sleepiness. Volumes of brain, ventricles, cerebellum, brainstem, cervical cord, lesion load and VBM results of the patient groups were compared to 33 matched healthy subjects. Results Clinical symptoms were depression (more pronounced in DM2), excessive daytime sleepiness (more pronounced in DM1), reduced attention and flexibility of thinking, and deficits of short-term memory and visuo-spatial abilities in both patient groups. Both groups showed ventricular enlargement and supratentorial GM and WM atrophy, with prevalence for more GM atrophy and involvement of the motor system in DM1 and more WM reduction and affection of limbic structures in DM2. White matter was reduced in DM1 in the splenium of the corpus callosum and in left-hemispheric WM adjacent to the pre- and post-central gyrus. In DM2, the bilateral cingulate gyrus and subgyral medio-frontal and primary somato-sensory WM was affected. Significant structural-functional correlations of morphological MRI findings (global volumetry and VBM) with clinical findings were found for reduced flexibility of thinking and atrophy of the left secondary visual cortex in DM1 and of distinct subcortical brain structures in DM2. In DM2, depression was associated with brainstem atrophy, Daytime sleepiness correlated with volume decrease in the middle cerebellar peduncles, pons/midbrain and the right medio-frontal cortex. Conclusion GM and WM atrophy was significant in DM1 and DM2. Specific functional-structural associations related morphological changes

  13. [Congenital muscular dystrophy with laminin-a2 deficiency in early infancy: diagnosis and long-term follow-up].

    PubMed

    Panteliadis, C; Karatza, E; Xinias, I; Flaris, N; Tzitiridou, M; Ramantani, G

    2005-01-01

    Congenital muscular dystrophy (CMD) is a heterogeneous group of neuromuscular disorders characterized by muscle weakness and hypotonia at birth or within the first few months of life. It is inherited in an autosomal recessive pattern. About half of the patients have a deficiency of the alpha-2-chain of laminin (merosin). We describe a case of congenital muscular dystrophy in an infant with laminin-a2-chain deficiency, which appeared hypotonia in early infancy. Diagnosis was made by clinical features and the histological and immunohistochemical studies on muscle biopsy.

  14. Genetics Home Reference: myotonic dystrophy

    MedlinePlus

    ... mutated gene produces an expanded version of messenger RNA , which is a molecular blueprint of the gene ... the production of proteins. The abnormally long messenger RNA forms clumps inside the cell that interfere with ...

  15. Reduced expression of sarcospan in muscles of Fukuyama congenital muscular dystrophy.

    PubMed

    Wakayama, Yoshihiro; Inoue, Masahiko; Kojima, Hiroko; Yamashita, Sumimasa; Shibuya, Seiji; Jimi, Takahiro; Hara, Hajime; Matsuzaki, Yoko; Oniki, Hiroaki; Kanagawa, Motoi; Kobayashi, Kazuhiro; Toda, Tatsushi

    2008-12-01

    Expression profiles of sarcospan in muscles with muscular dystrophies are scarcely reported. To examine this, we studied five Fukuyama congenital muscular dystrophy (FCMD) muscles, five Duchenne muscular dystrophy (DMD) muscles, five disease control and five normal control muscles. Immunoblot showed reactions of sarcospan markedly decreased in FCMD and DMD muscle extracts. Immunohistochemistry of FCMD muscles showed that most large diameter myofibers expressed sarcospan discontinuously at their surface membranes. Immature small diameter FCMD myofibers usually did not express sarcospan. Immunoreactivity of sarcospan in DMD muscles was similarly reduced. With regard to dystroglycans and sarcoglycans, immunohistochemistry of FCMD muscles showed selective deficiency of glycosylated alpha-dystroglycan, together with reduced expression of beta-dystroglycan and alpha-, beta-, gamma-, delta-sarcoglycans. Although the expression of glycosylated alpha-dystroglycan was lost, scattered FCMD myofibers showed positive immunoreaction with an antibody against the core protein of alpha-dystroglycan. The group mean ratios of sarcospan mRNA copy number versus GAPDH mRNA copy number by real-time RT-PCR showed that the ratios between FCMD and normal control groups were not significantly different (P>0.1 by the two-tailed t test). This study implied either O-linked glycosylation defects of alpha-dystroglycan in the Golgi apparatus of FCMD muscles may lead to decreased expression of sarcoglycan and sarcospan molecules, or selective deficiency of glycosylated alpha-dystroglycan due to impaired glycosylation in FCMD muscles may affect the molecular integrity of the basal lamina of myofibers. This, in turn, leads to decreased expression of sarcoglycans, and finally of sarcospan at the FCMD myofiber surfaces.

  16. From "glycosyltransferase" to "congenital muscular dystrophy": integrating knowledge from NCBI Entrez Gene and the Gene Ontology.

    PubMed

    Sahoo, Satya S; Zeng, Kelly; Bodenreider, Olivier; Sheth, Amit

    2007-01-01

    Entrez Gene (EG), Online Mendelian Inheritance in Man (OMIM) and the Gene Ontology (GO) are three complementary knowledge resources that can be used to correlate genomic data with disease information. However, bridging between genotype and phenotype through these resources currently requires manual effort or the development of customized software. In this paper, we argue that integrating EG and GO provides a robust and flexible solution to this problem. We demonstrate how the Resource Description Framework (RDF) developed for the Semantic Web can be used to represent and integrate these resources and enable seamless access to them as a unified resource. We illustrate the effectiveness of our approach by answering a real-world biomedical query linking a specific molecular function, glycosyltransferase, to the disorder congenital muscular dystrophy.

  17. Deficiency of merosin in dystrophic dy mouse homologue of congenital muscular dystrophy

    SciTech Connect

    Sunada, Y.; Campbell, K.P.; Bernier, S.M.

    1994-09-01

    Merosin (laminin M chain) is the predominant laminin isoform in the basal lamina of striated muscle and peripheral nerve and is a native ligand for {alpha}-dystroglycan, a novel laminin receptor. Merosin is linked to the subsarcolemmal actin cytoskeleton via the dystrophin-glycoprotein complex (DGC), which plays an important role for maintenance of normal muscle function. We have mapped the mouse merosin gene, Lamm, to the region containing the dystrophia muscularis (dy) locus on chromosome 10. This suggested the possibility that a mutation in the merosin gene could be responsible for the dy mouse, an animal model for autosomal recessive muscular dystrophy, and prompted us to test this hypothesis. We analyzed the status of merosin expression in dy mouse by immunofluorescence and immunoblotting. In dy mouse skeletal and cardiac muscle and peripheral nerve, merosin was reduced greater than 90% as compared to control mice. However, the expression of laminin B1/B2 chains and collagen type IV was smaller to that in control mice. These findings strongly suggest that merosin deficiency may be the primary defect in the dy mouse. Furthermore, we have identified two patients afflicted with congenital muscular dystrophy with merosin deficiency, providing the basis for future studies of molecular pathogenesis and gene therapy.

  18. Molecular genetic evidence of clinical heterogeneity in Fukuyama-type congenital muscular dystrophy.

    PubMed

    Kondo-Iida, E; Saito, K; Tanaka, H; Tsuji, S; Ishihara, T; Osawa, M; Fukuyama, Y; Toda, T

    1997-04-01

    Fukuyama-type congenital muscular dystrophy (FCMD) is an autosomal recessive severe muscular dystrophy associated with brain malformation. The gene responsible for FCMD was mapped to chromosome 9q31, a region in which convincing evidence of strong linkage disequilibrium between FCMD and mfd220 (D9S306) was recently found. FCMD is also characterized clinically by a peak motor function which, at best, allows patients to sit unassisted or slide on the buttocks. However, a small fraction of patients acquire the capacity to walk unassisted. Whether such ambulant cases belong to the FCMD spectrum or to a different disease entity has been a topic of considerable debate. We performed linkage analysis for ten families with ambulant cases using DNA markers flanking the FCMD locus. The mfd220 locus yielded a significant lod score of 3.09 for ambulant FCMD. We also found evidence for linkage disequilibrium between ambulant FCMD and mfd220. We further conducted haplotype analysis in FCMD siblings with different phenotypes, one of whom was ambulant while the other was not. The results indicate that the FCMD siblings share exactly the same haplotype at nine marker loci spanning 23.3 cM surrounding the FCMD locus. On the basis of these results, we conclude that, genetically, ambulant cases are, in fact, part of the FCMD spectrum.

  19. Model organisms in the fight against muscular dystrophy: lessons from drosophila and Zebrafish.

    PubMed

    Plantié, Emilie; Migocka-Patrzałek, Marta; Daczewska, Małgorzata; Jagla, Krzysztof

    2015-01-01

    Muscular dystrophies (MD) are a heterogeneous group of genetic disorders that cause muscle weakness, abnormal contractions and muscle wasting, often leading to premature death. More than 30 types of MD have been described so far; those most thoroughly studied are Duchenne muscular dystrophy (DMD), myotonic dystrophy type 1 (DM1) and congenital MDs. Structurally, physiologically and biochemically, MDs affect different types of muscles and cause individual symptoms such that genetic and molecular pathways underlying their pathogenesis thus remain poorly understood. To improve our knowledge of how MD-caused muscle defects arise and to find efficacious therapeutic treatments, different animal models have been generated and applied. Among these, simple non-mammalian Drosophila and zebrafish models have proved most useful. This review discusses how zebrafish and Drosophila MD have helped to identify genetic determinants of MDs and design innovative therapeutic strategies with a special focus on DMD, DM1 and congenital MDs. PMID:25859781

  20. Model organisms in the fight against muscular dystrophy: lessons from drosophila and Zebrafish.

    PubMed

    Plantié, Emilie; Migocka-Patrzałek, Marta; Daczewska, Małgorzata; Jagla, Krzysztof

    2015-04-09

    Muscular dystrophies (MD) are a heterogeneous group of genetic disorders that cause muscle weakness, abnormal contractions and muscle wasting, often leading to premature death. More than 30 types of MD have been described so far; those most thoroughly studied are Duchenne muscular dystrophy (DMD), myotonic dystrophy type 1 (DM1) and congenital MDs. Structurally, physiologically and biochemically, MDs affect different types of muscles and cause individual symptoms such that genetic and molecular pathways underlying their pathogenesis thus remain poorly understood. To improve our knowledge of how MD-caused muscle defects arise and to find efficacious therapeutic treatments, different animal models have been generated and applied. Among these, simple non-mammalian Drosophila and zebrafish models have proved most useful. This review discusses how zebrafish and Drosophila MD have helped to identify genetic determinants of MDs and design innovative therapeutic strategies with a special focus on DMD, DM1 and congenital MDs.

  1. Delayed onset of congenital hereditary endothelial dystrophy due to compound heterozygous SLC4A11 mutations

    PubMed Central

    Kumawat, Babu Lal; Gupta, Ranjan; Sharma, Arundhati; Sen, Seema; Gupta, Shikha; Tandon, Radhika

    2016-01-01

    Background: Congenital hereditary endothelial dystrophy (CHED) is an autosomal recessive disorder characterized by bilateral, symmetrical, noninflammatory corneal clouding (edema) present at birth or shortly thereafter. This study reports on an unusual delayed presentation of CHED with compound heterozygous SLC4A11 mutations. Materials and Methods: A 45-year-old female, presenting with bilateral decreased vision since childhood that deteriorated in the last 5 years, was evaluated to rule out trauma, viral illness, chemical injury, glaucoma, and corneal endothelial dystrophies. Tear sample was sent for herpes simplex viral (HSV) antigen testing. Genomic DNA from peripheral blood was screened for mutations in all exons of SLC4A11 by direct sequencing. Full-thickness penetrating keratoplasty was done and corneal button was sent for histopathological examination. Results: Slit-lamp findings revealed bilateral diffuse corneal edema and left eye spheroidal degeneration with scarring. Increased corneal thickness (762 μm and 854 μm in the right and left eyes, respectively), normal intraocular pressure (12 mmHg and 16 mmHg in the right and left eyes, respectively), inconclusive confocal scan, and specular microscopy, near normal tear film parameters, were the other clinical features. HSV-polymerase chain reaction was negative. Histopathological examination revealed markedly thickened Descemet's membrane with subepithelial spheroidal degeneration. SLC4A11 screening showed a novel variant p.Ser415Asn, reported mutation p.Cys386Arg and two polymorphisms, all in the heterozygous state and not identified in 100 controls. Conclusions: The study shows, for the first time, compound heterozygous SLC4A11 mutations impair protein function leading to delayed onset of the disease. PMID:27609159

  2. SLC4A11 and the Pathophysiology of Congenital Hereditary Endothelial Dystrophy.

    PubMed

    Patel, Sangita P; Parker, Mark D

    2015-01-01

    Congenital hereditary endothelial dystrophy (CHED) is a rare autosomal recessive disorder of the corneal endothelium characterized by nonprogressive bilateral corneal edema and opacification present at birth. Here we review the current knowledge on the role of the SLC4A11 gene, protein, and its mutations in the pathophysiology and clinical presentation of CHED. Individuals with CHED have mutations in SLC4A11 which encodes a transmembrane protein in the SLC4 family of bicarbonate transporters. The expression of SLC4A11 in the corneal endothelium and inner ear patterns the deficits seen in CHED with corneal edema and hearing loss (Harboyan syndrome). slc4a11-null-mouse models recapitulate the CHED disease phenotype, thus establishing a functional role for SLC4A11 in CHED. However, the transport function of SLC4A11 remains unsettled. Some of the roles that have been attributed to SLC4A11 include H(+) and NH4 (+) permeation, electrogenic Na(+)-H(+) exchange, and water transport. Future studies of the consequences of SLC4A11 dysfunction as well as further understanding of corneal endothelial ion transport will help clarify the involvement of SLC4A11 in the pathophysiology of CHED. PMID:26451371

  3. The value of respiratory muscle testing in a child with congenital muscular dystrophy

    PubMed Central

    Khirani, Sonia; Dabaj, Ivana; Amaddeo, Alessandro; Ramirez, Adriana; Quijano-Roy, Susana; Fauroux, Brigitte

    2014-01-01

    Respiratory muscle testing is often limited to noninvasive volitional tests such as vital capacity and maximal static pressures. We report the case of a 12-year-old boy with congenital muscular dystrophy (CMD) in whom invasive and non-volitional respiratory muscle tests showed an elective diaphragmatic dysfunction with the preservation of expiratory muscle strength. This finding, coupled with a clinical phenotype associating diffuse muscle atrophy with finger hyperlaxity and proximal contractures, strengthened the suspicion of Ullrich CMD. Skin-cultured fibroblasts showed intracellular retention of collagen 6 (COL6), muscle magnetic resonance imaging was typical of COL6 myopathy, and molecular studies identified a COL6 gene mutation (COL6A2 c.954+2T>C). The diagnosis of a diaphragmatic dysfunction led to a sleep study that evidenced periods of hypoxemia which justified nocturnal noninvasive ventilation. This case report highlights the benefit of assessing respiratory muscles, through invasive procedure, to assist in clinical diagnosis and to guide clinical management. PMID:25473580

  4. Role of Decorin Core Protein in Collagen Organisation in Congenital Stromal Corneal Dystrophy (CSCD)

    PubMed Central

    Kamma-Lorger, Christina S.; Pinali, Christian; Martínez, Juan Carlos; Harris, Jon; Young, Robert D.; Bredrup, Cecilie; Crosas, Eva; Malfois, Marc; Rødahl, Eyvind

    2016-01-01

    The role of Decorin in organising the extracellular matrix was examined in normal human corneas and in corneas from patients with Congenital Stromal Corneal Dystrophy (CSCD). In CSCD, corneal clouding occurs due to a truncating mutation (c.967delT) in the decorin (DCN) gene. Normal human Decorin protein and the truncated one were reconstructed in silico using homology modelling techniques to explore structural changes in the diseased protein. Corneal CSCD specimens were also examined using 3-D electron tomography and Small Angle X-ray diffraction (SAXS), to image the collagen-proteoglycan arrangement and to quantify fibrillar diameters, respectively. Homology modelling showed that truncated Decorin had a different spatial geometry to the normal one, with the truncation removing a major part of the site that interacts with collagen, compromising its ability to bind effectively. Electron tomography showed regions of abnormal stroma, where collagen fibrils came together to form thicker fibrillar structures, showing that Decorin plays a key role in the maintenance of the order in the normal corneal extracellular matrix. Average diameter of individual fibrils throughout the thickness of the cornea however remained normal. PMID:26828927

  5. Immuno-electron labelling of matrix components in congenital hereditary endothelial dystrophy.

    PubMed

    Sekundo, W; Marshall, G E; Lee, W R; Kirkness, C M

    1994-06-01

    Two corneal buttons were obtained from a patient with congenital hereditary endothelial dystrophy (CHED) at the ages of 2.5 years (right eye) and 14 years (left eye) and were studied by light and electron microscopy including immunogold labelling for collagen types I-V and laminin. The posterior collagenous layer (PCL) of Descemet's membrane contained collagen types I, III-V, and laminin: the latter was also localised to fine-banded and granular material in the posterior non-banded zone (PNBZ). Comparison of the endothelium 2.5 years and 14 years revealed occasional dystrophic changes in the former and extensive dystrophic changes in the latter. The distribution of collagen types I, III and V within the PCL supports previous morphological observations of fibroblast-like change of the endothelium in CHED. Persisting endothelial properties were manifest as positive labelling of type IV collagen and laminin. An excessive amount of laminin found in PNBZ and PCL is another stress-related endothelial reaction.

  6. Behavioral Responses in Animal Model of Congenital Muscular Dystrophy 1D.

    PubMed

    Comim, Clarissa M; Schactae, Aryadnne L; Soares, Jaime A; Ventura, Letícia; Freiberger, Viviane; Mina, Francielle; Dominguini, Diogo; Vainzof, Mariz; Quevedo, João

    2016-01-01

    Congenital muscular dystrophies 1D (CMD1D) present a mutation on the LARGE gene and are characterized by an abnormal glycosylation of α-dystroglycan (α-DG), strongly implicated as having a causative role in the development of central nervous system abnormalities such as cognitive impairment seen in patients. However, in the animal model of CMD1D, the brain involvement remains unclear. Therefore, the objective of this study is to evaluate the cognitive involvement in the Large(myd) mice. To this aim, we used adult homozygous, heterozygous, and wild-type mice. The mice underwent six behavioral tasks: habituation to an open field, step-down inhibitory avoidance, continuous multiple trials step-down inhibitory avoidance task, object recognition, elevated plus-maze, and forced swimming test. It was observed that Large(myd) individuals presented deficits on the habituation to the open field, step down inhibitory avoidance, continuous multiple-trials step-down inhibitory avoidance, object recognition, and forced swimming. This study shows the first evidence that abnormal glycosylation of α-DG may be affecting memory storage and restoring process in an animal model of CMD1D.

  7. SLC4A11 and the Pathophysiology of Congenital Hereditary Endothelial Dystrophy

    PubMed Central

    Patel, Sangita P.; Parker, Mark D.

    2015-01-01

    Congenital hereditary endothelial dystrophy (CHED) is a rare autosomal recessive disorder of the corneal endothelium characterized by nonprogressive bilateral corneal edema and opacification present at birth. Here we review the current knowledge on the role of the SLC4A11 gene, protein, and its mutations in the pathophysiology and clinical presentation of CHED. Individuals with CHED have mutations in SLC4A11 which encodes a transmembrane protein in the SLC4 family of bicarbonate transporters. The expression of SLC4A11 in the corneal endothelium and inner ear patterns the deficits seen in CHED with corneal edema and hearing loss (Harboyan syndrome). slc4a11-null-mouse models recapitulate the CHED disease phenotype, thus establishing a functional role for SLC4A11 in CHED. However, the transport function of SLC4A11 remains unsettled. Some of the roles that have been attributed to SLC4A11 include H+ and NH4+ permeation, electrogenic Na+-H+ exchange, and water transport. Future studies of the consequences of SLC4A11 dysfunction as well as further understanding of corneal endothelial ion transport will help clarify the involvement of SLC4A11 in the pathophysiology of CHED. PMID:26451371

  8. Apoptosis inhibitors and mini-agrin have additive benefits in congenital muscular dystrophy mice

    PubMed Central

    Meinen, Sarina; Lin, Shuo; Thurnherr, Raphael; Erb, Michael; Meier, Thomas; Rüegg, Markus A

    2011-01-01

    Mutations in LAMA2 cause a severe form of congenital muscular dystrophy, called MDC1A. Studies in mouse models have shown that transgenic expression of a designed, miniaturized form of the extracellular matrix molecule agrin (‘mini-agrin’) or apoptosis inhibition by either overexpression of Bcl2 or application of the pharmacological substance omigapil can ameliorate the disease. Here, we tested whether mini-agrin and anti-apoptotic agents act on different pathways and thus exert additive benefits in MDC1A mouse models. By combining mini-agrin with either transgenic Bcl2 expression or oral omigapil application, we show that the ameliorating effect of mini-agrin, which acts by restoring the mechanical stability of muscle fibres and, thereby, reduces muscle fibre breakdown and concomitant fibrosis, is complemented by apoptosis inhibitors, which prevent the loss of muscle fibres. Treatment of mice with both agents results in improved muscle regeneration and increased force. Our results show that the combination of mini-agrin and anti-apoptosis treatment has beneficial effects that are significantly bigger than the individual treatments and suggest that such a strategy might also be applicable to MDC1A patients. PMID:21674808

  9. SLC4A11 and the Pathophysiology of Congenital Hereditary Endothelial Dystrophy.

    PubMed

    Patel, Sangita P; Parker, Mark D

    2015-01-01

    Congenital hereditary endothelial dystrophy (CHED) is a rare autosomal recessive disorder of the corneal endothelium characterized by nonprogressive bilateral corneal edema and opacification present at birth. Here we review the current knowledge on the role of the SLC4A11 gene, protein, and its mutations in the pathophysiology and clinical presentation of CHED. Individuals with CHED have mutations in SLC4A11 which encodes a transmembrane protein in the SLC4 family of bicarbonate transporters. The expression of SLC4A11 in the corneal endothelium and inner ear patterns the deficits seen in CHED with corneal edema and hearing loss (Harboyan syndrome). slc4a11-null-mouse models recapitulate the CHED disease phenotype, thus establishing a functional role for SLC4A11 in CHED. However, the transport function of SLC4A11 remains unsettled. Some of the roles that have been attributed to SLC4A11 include H(+) and NH4 (+) permeation, electrogenic Na(+)-H(+) exchange, and water transport. Future studies of the consequences of SLC4A11 dysfunction as well as further understanding of corneal endothelial ion transport will help clarify the involvement of SLC4A11 in the pathophysiology of CHED.

  10. Nutritional status evaluation in patients affected by bethlem myopathy and ullrich congenital muscular dystrophy.

    PubMed

    Toni, Silvia; Morandi, Riccardo; Busacchi, Marcello; Tardini, Lucia; Merlini, Luciano; Battistini, Nino Carlo; Pellegrini, Massimo

    2014-01-01

    Collagen VI mutations lead to disabling myopathies like Bethlem myopathy (BM) and Ullrich congenital muscular dystrophy (UCMD). We have investigated the nutritional and metabolic status of one UCMD and seven BM patients (five female, three male, mean age 31 ± 9 years) in order to find a potential metabolic target for nutritional intervention. For this study, we used standard anthropometric tools, such as BMI evaluation and body circumference measurements. All results were compared to dual-energy X-ray absorptiometry (DXA), considered the "gold standard" method. Energy intake of each patient was evaluated through longitudinal methods (7-day food diary) while resting energy expenditure (REE) was predicted using specific equations and measured by indirect calorimetry. Clinical evaluation included general and nutritional blood and urine laboratory analyses and quantitative muscle strength measurement by hand-held dynamometry. BM and UCMD patients showed an altered body composition, characterized by low free fat mass (FFM) and high fat mass (FM), allowing us to classify them as sarcopenic, and all but one as sarcopenic-obese. Another main result was the negative correlation between REE/FFM ratio (basal energy expenditure per kilograms of fat-free mass) and the severity of the disease, as defined by the muscle megascore (correlation coefficient -0.955, P-value <0.001). We postulate that the increase of the REE/FFM ratio in relation to the severity of the disease may be due to an altered and pathophysiological loss of energetic efficiency at the expense of skeletal muscle. We show that a specific metabolic disequilibrium is related to the severity of the disease, which may represent a target for a nutritional intervention in these patients. PMID:25477818

  11. Mutations in COL6A3 Cause Severe and Mild Phenotypes of Ullrich Congenital Muscular Dystrophy

    PubMed Central

    Demir, Ercan; Sabatelli, Patrizia; Allamand, Valérie; Ferreiro, Ana; Moghadaszadeh, Behzad; Makrelouf, Mohamed; Topaloglu, Haluk; Echenne, Bernard; Merlini, Luciano; Guicheney, Pascale

    2002-01-01

    Ullrich congenital muscular dystrophy (UCMD) is an autosomal recessive disorder characterized by generalized muscular weakness, contractures of multiple joints, and distal hyperextensibility. Homozygous and compound heterozygous mutations of COL6A2 on chromosome 21q22 have recently been shown to cause UCMD. We performed a genomewide screening with microsatellite markers in a consanguineous family with three sibs affected with UCMD. Linkage of the disease to chromosome 2q37 was found in this family and in two others. We analyzed COL6A3, which encodes the α3 chain of collagen VI, and identified one homozygous mutation per family. In family I, the three sibs carried an A→G transition in the splice-donor site of intron 29 (6930+5A→G), leading to the skipping of exon 29, a partial reduction of collagen VI in muscle biopsy, and an intermediate phenotype. In family II, the patient had an unusual mild phenotype, despite a nonsense mutation, R465X, in exon 5. Analysis of the patient’s COL6A3 transcripts showed the presence of various mRNA species—one of which lacked several exons, including the exon containing the nonsense mutation. The deleted splice variant encodes collagen molecules that have a shorter N-terminal domain but that may assemble with other chains and retain a functional role. This could explain the mild phenotype of the patient who was still ambulant at age 18 years and who showed an unusual combination of hyperlaxity and finger contractures. In family III, the patient had a nonsense mutation, R2342X, causing absence of collagen VI in muscle and fibroblasts, and a severe phenotype, as has been described in patients with UCMD. Mutations in COL6A3 are described in UCMD for the first time and illustrate the wide spectrum of phenotypes which can be caused by collagen VI deficiency. PMID:11992252

  12. Refined mapping of a gene responsible for Fukuyama-type congenital muscular dystrophy: Evidence for strong linkage disequilibrium

    SciTech Connect

    Toda, Tatsushi; Ikegawa, Shiro; Okui, Keiko; Nakamura, Yusuke; Kanazawa, Ichiro; Kondo, Eri; Saito, Kayoko; Fukuyama, Yukio; Yoshioka, Mieko; Kumagai, Toshiyuki

    1994-11-01

    Fukuyama-type congenital muscular dystrophy (FCMD), the second most common form of childhood muscular dystrophy in Japan, is an autosomal recessive severe muscular dystrophy associated with an anomaly of the brain. After our initial mapping of the FCMD locus to chromosome 9q31-33, we further defined the locus within a region of {approximately}5 cM between loci D9S127 and CA246, by homozygosity mapping in patients born to consanguineous marriages and by recombination analyses in other families. We also found evidence for strong linkage disequilibrium between FCMD and a polymorphic microsatellite marker, mfd220, which showed no recombination and a lod score of (Z) 17.49. A {open_quotes}111-bp{close_quotes} allele for the mfd220 was observed in 22 (34%) of 64 FCMD chromosomes, but it was present in only 1 of 120 normal chromosomes. This allelic association with FCMD was highly significant ({chi}{sup 2} = 50.7; P < .0001). Hence, we suspect that the FCMD gene could lie within a few hundred kilobases of the mfd220 locus. 32 refs., 2 figs., 2 tabs.

  13. Whole Exome Sequencing Reveals DYSF, FKTN, and ISPD Mutations in Congenital Muscular Dystrophy Without Brain or Eye Involvement

    PubMed Central

    Ceyhan-Birsoy, Ozge; Talim, Beril; Swanson, Lindsay C.; Karakaya, Mert; Graff, Michelle A.; Beggs, Alan H.; Topaloglu, Haluk

    2015-01-01

    Background Congenital muscular dystrophies (CMDs) are a genetically and clinically heterogeneous group of neuromuscular disorders. Several genes encoding extracellular matrix, nuclear envelope, sarcolemmal proteins and glycosylation enzymes have been implicated in CMDs. The large overlap of clinical presentations due to mutations in different genes poses a challenge for clinicians in determining disease etiology for each patient. Objective We investigated the use of whole exome sequencing (WES) in identifying the genetic cause of disease in 5 CMD patients from 3 families who presented with highly similar clinical features, including early-onset rapidly progressive weakness without brain or eye abnormalities. Methods Whole exome sequencing was performed on DNA from affected individuals. Potential functional impacts of mutations were investigated by immunostaining on available muscle biopsies. Results Pathogenic mutations in 3 different genes, DYSF, FKTN, and ISPD were identified in each family. Mutation in DYSF led to absence of dysferlin protein in patient muscle. Mutations in ISPD led to impaired ISDP function, as demonstrated by deficiency of α-dystroglycan glycosylation in patient muscle. Conclusions This study highlights the benefit of unbiased genomic approaches in molecular diagnosis of neuromuscular disorders with high clinical heterogeneity, such as the phenotypes observed in our patients. Our results suggest that dysferlin deficiency should be in the differential diagnosis of congenital and rapidly progressive muscular dystrophy, and therefore dysferlin antibody should be in the standard immunohistochemistry panel for muscle biopsies in cases with suspected CMD. PMID:25821721

  14. An Open-Label Trial of Recombinant Human Insulin-Like Growth Factor-I/Recombinant Human Insulin-Like Growth Factor Binding Protein-3 (rhIGF-1/rhIGFBP-3) in Myotonic Dystrophy Type 1

    PubMed Central

    Heatwole, Chad R.; Eichinger, Katy J.; Friedman, Deborah I.; Hilbert, James E.; Jackson, Carlayne E.; Logigian, Eric L.; Martens, William B.; McDermott, Michael P.; Pandya, Shree K.; Quinn, Christine; Smirnow, Alexis M.; Thornton, Charles A.; Moxley, Richard T.

    2012-01-01

    Objective To evaluate the safety and tolerability of recombinant human insulin-like growth factor-1 (rhIGF-1) complexed with IGF binding protein-3 (rhIGF-1/rhIGFBP-3) in patients with myotonic dystrophy type 1 (DM1). Design Open-label dose-escalation clinical trial. Setting University medical center. Participants Fifteen moderately affected ambulatory participants with genetically-proven DM1. Intervention Participants received escalating dosages of subcutaneous rhIGF-1/rhIGFBP-3 over 24 weeks followed by a 16 week washout period. Outcome Measures Serial assessments of safety, muscle mass, muscle function, and metabolic state were performed. The primary outcome variable was the ability of participants to complete 24 weeks on rhIGF-1/rhIGFBP-3 treatment. Results All participants tolerated rhIGF-1/rhIGFBP-3. There were no significant changes in muscle strength or functional outcomes measures. Lean body muscle mass measured by dual energy x-ray absorptiometry increased by 1.95 kg (p=0.0007) after treatment. Participants also experienced a mean reduction in triglyceride levels of 47 mg/dL (p=0.002), a mean increase in HDL levels of 5.0 mg/dL (p=0.03), a mean reduction in HbA1c of 0.15% (p=0.03), and a mean increase in testosterone level (in men) of 203 ng/dL (p=0.002) while on rhIGF-1/rhIGFBP-3. Mild reactions at the injection site occurred (n=9 participants), as did mild transient hypoglycemia (n=3), lightheadedness (n=2), and transient papilledema (n=1). Conclusions rhIGF-1/rhIGFBP-3 treatment was generally well tolerated in DM1. rhIGF-1/rhIGFBP-3 was associated with increased lean body mass and improvements in metabolism, but not with increased muscle strength or function. Larger randomized controlled trials would be needed to further evaluate the efficacy and safety of this medication in patients with neuromuscular disease. PMID:20837825

  15. YAC and cosmid contigs encompassing the Fukuyama-type congenital muscular dystrophy (FCMD) candidate region on 9q31

    SciTech Connect

    Miyake, Masashi; Nakahori, Yutaka; Matsushita, Ikumi

    1997-03-01

    Fukuyama-type congenital muscular dystrophy (FCMD), the second most common form of childhood muscular dystrophy in Japan, is an autosomal recessive severe muscular dystrophy associated with an anomaly of the brain. We had mapped the FCMD gene to an approximately 5-cM interval between D9S127 and D9S2111 on 9q31-q33 and had also found evidence for linkage disequilibrium between FCMD and D9S306 in this candidate region. Through further analysis, we have defined another marker, D9S172, which showed stronger linkage disequilibrium than D9S306. A yeast artificial chromosome (YAC) contig spanning 3.5 Mb, which includes this D9S306-D9S172 interval on 9q31, has been constructed by a combination of sequence-tagged site, Alu-PCR, and restriction mapping. Also, cosmid clones subcloned from the YAC were assembled into three contigs, one of which contains D9S2107, which showed the strongest linkage disequilibrium with FCMD. These contigs also allowed us to order the markers as follows: cen-D9S127-({approximately}800 kb)-D9S306 (identical to D9S53)-({approximately}700 kb)-A107XF9-({approximately}500 kb)-D9S172-({approximately}30 kb)-D9S299 (identical to D9S774)-({approximately}120 kb)-WI2269-tel. Thus, we have constructed the first high-resolution physical map of the FCMD candidate region. The YAC and cosmid contigs established here will be a crucial resource for identification of the FCMD gene and other genes in this region. 37 refs., 7 figs., 2 tabs.

  16. Carrell-Krusen Symposium Invited Lecture-1997. Myotonic disorders in childhood: diagnosis and treatment.

    PubMed

    Moxley, R T

    1997-02-01

    The recent discoveries that mutations in the genes for the skeletal muscle sodium and chloride channels are responsible, respectively, for paramyotonia/hyperkalemic periodic paralysis and for myotonia congenita of Thomsen have made the classification, diagnosis, and treatment of these disorders much easier. The discovery that myotonic dystrophy results from an unstable [CTG]n trinucleotide expansion has permitted the accurate diagnosis of both symptomatic and asymptomatic individuals, and has led to major advances in preventive treatment, including prenatal and genetic counseling. Diseases that resemble the inherited myotonic disorders are now easier to identify, and as a result of genetic testing a new clinical disorder that is similar to but distinct from myotonic dystrophy has emerged. This new disorder, proximal myotonic myopathy, does not appear to be linked to the genes for the sodium or chloride channels, and has cataracts, myotonia, weakness, and no abnormal expansion of the [CTG]n repeat in the gene for myotonic dystrophy. This review discusses the diagnosis and treatment of these myotonic disorders. PMID:9075021

  17. Transcriptome Analysis of Ullrich Congenital Muscular Dystrophy Fibroblasts Reveals a Disease Extracellular Matrix Signature and Key Molecular Regulators

    PubMed Central

    Rodríguez, Maria Angels; Jou, Cristina; Puigdelloses, Montserrat; Ortez, Carlos I.; Diaz-Manera, Jordi; Gallardo, Eduardo; Colomer, Jaume; Nascimento, Andrés; Kalko, Susana G.; Jimenez-Mallebrera, Cecilia

    2015-01-01

    Background Collagen VI related myopathies encompass a range of phenotypes with involvement of skeletal muscle, skin and other connective tissues. They represent a severe and relatively common form of congenital disease for which there is no treatment. Collagen VI in skeletal muscle and skin is produced by fibroblasts. Aims & Methods In order to gain insight into the consequences of collagen VI mutations and identify key disease pathways we performed global gene expression analysis of dermal fibroblasts from patients with Ullrich Congenital Muscular Dystrophy with and without vitamin C treatment. The expression data were integrated using a range of systems biology tools. Results were validated by real-time PCR, western blotting and functional assays. Findings We found significant changes in the expression levels of almost 600 genes between collagen VI deficient and control fibroblasts. Highly regulated genes included extracellular matrix components and surface receptors, including integrins, indicating a shift in the interaction between the cell and its environment. This was accompanied by a significant increase in fibroblasts adhesion to laminin. The observed changes in gene expression profiling may be under the control of two miRNAs, miR-30c and miR-181a, which we found elevated in tissue and serum from patients and which could represent novel biomarkers for muscular dystrophy. Finally, the response to vitamin C of collagen VI mutated fibroblasts significantly differed from healthy fibroblasts. Vitamin C treatment was able to revert the expression of some key genes to levels found in control cells raising the possibility of a beneficial effect of vitamin C as a modulator of some of the pathological aspects of collagen VI related diseases. PMID:26670220

  18. Therapeutic advances in muscular dystrophy

    PubMed Central

    Leung, Doris G; Wagner, Kathryn R

    2013-01-01

    The muscular dystrophies comprise a heterogeneous group of genetic disorders that produce progressive skeletal muscle weakness and wasting. There has been rapid growth and change in our understanding of these disorders in recent years, and advances in basic science are being translated into increasing numbers of clinical trials. This review will discuss therapeutic developments in 3 of the most common forms of muscular dystrophy: Duchenne muscular dystrophy, facioscapulohumeral muscular dystrophy, and myotonic dystrophy. Each of these disorders represents a different class of genetic disease (monogenic, epigenetic, and repeat expansion disorders), and the approach to therapy addresses the diverse and complex molecular mechanisms involved in these diseases. The large number of novel pharmacologic agents in development with good biologic rationale and strong proof of concept suggests there will be an improved quality of life for individuals with muscular dystrophy. PMID:23939629

  19. European Home Mechanical Ventilation Registry

    ClinicalTrials.gov

    2016-10-25

    Pulmonary Disease, Chronic Obstructive; Amyotrophic Lateral Sclerosis; Spinal Cord Injury; Muscular Dystrophies; Obesity Hypoventilation Syndrome; Kyphoscoliosis; Congenital Central Hypoventilation Syndrome; Duchenne Muscular Dystrophy; Myopathies; Myotonic Dystrophy

  20. Air stacking: effects on pulmonary function in patients with spinal muscular atrophy and in patients with congenital muscular dystrophy*,**

    PubMed Central

    Marques, Tanyse Bahia Carvalho; Neves, Juliana de Carvalho; Portes, Leslie Andrews; Salge, João Marcos; Zanoteli, Edmar; Reed, Umbertina Conti

    2014-01-01

    OBJECTIVE: Respiratory complications are the main causes of morbidity and mortality in patients with neuromuscular disease (NMD). The objectives of this study were to determine the effects that routine daily home air-stacking maneuvers have on pulmonary function in patients with spinal muscular atrophy (SMA) and in patients with congenital muscular dystrophy (CMD), as well as to identify associations between spinal deformities and the effects of the maneuvers. METHODS: Eighteen NMD patients (ten with CMD and eight with SMA) were submitted to routine daily air-stacking maneuvers at home with manual resuscitators for four to six months, undergoing pulmonary function tests before and after that period. The pulmonary function tests included measurements of FVC; PEF; maximum insufflation capacity (MIC); and assisted and unassisted peak cough flow (APCF and UPCF, respectively) with insufflations. RESULTS: After the use of home air-stacking maneuvers, there were improvements in the APCF and UPCF. In the patients without scoliosis, there was also a significant increase in FVC. When comparing patients with and without scoliosis, the increases in APCF and UPCF were more pronounced in those without scoliosis. CONCLUSIONS: Routine daily air-stacking maneuvers with a manual resuscitator appear to increase UPCF and APCF in patients with NMD, especially in those without scoliosis. PMID:25410841

  1. Decreased expression of myotonin-protein kinase messenger RNA and protein in adult form of myotonic dystropy

    SciTech Connect

    Yinghui Fu; Friedman, D.L.; Richards, S.; Pearlman, J.A.; Gibbs, R.A.; Pizzuti, A.; Perryman, M.B.; Fenwick, R.G. Jr.; Caskey, C.T. ); Ashizawa, Tetsuo Veterans Administration Medical Center, Houston, TX ); Scarlato, G. )

    1993-04-09

    The myotonic dystrophy mutation has recently been identified; however, the molecular mechanism of the disease is still unknown. The sequence of the myotonin-protein kinase gene was determined, and messenger RNA spliced forms were identified in various tissues. Antisera were developed for analytical studies. Quantitative reverse transcription-polymerase chain reaction and radioimmunoassay were used to demonstrate that decreased levels of the messenger RNA and protein expression are associated with adult form of myotonic dystropy. 12 refs., 5 figs.

  2. Possible influences on the expression of X chromosome-linked dystrophin abnormalities by heterozygosity for autosomal recessive Fukuyama congenital muscular dystrophy

    SciTech Connect

    Beggs, A.H.; Neumann, P.E.; Anderson, M.S.; Kunkel, L.M. ); Arahata, Kiichi; Arikawa, Eri; Nonaka, Ikuya )

    1992-01-15

    Abnormalities of dystrophin, a cytoskeletal protein of muscle and nerve, are generally considered specific for Duchenne and Becker muscular dystrophy. However, several patients have recently been identified with dystrophin deficiency who, before dystrophin testing, were considered to have Fukuyama congenital muscular dystrophy (FCMD) on the basis of clinical findings. Epidemiologic data suggest that only 1/3,500 males with autosomal recessive FCMD should have abnormal dystrophin. To explain the observation of 3/23 FCMD males with abnormal dystrophin, the authors propose that dystrophin and the FCMD gene product interact and that the earlier onset and greater severity of these patients' phenotype (relative to Duchenne muscular dystrophy) are due to their being heterozygous for the FCMD mutation in addition to being hemizygous for Duchenne muscular dystrophy, a genotype that is predicted to occur in 1/175,000 Japanese males. This model may help explain the genetic basis for some of the clinical and pathological variability seen among patients with FCMD, and it has potential implications for understanding the inheritance of other autosomal recessive disorders in general. For example, sex ratios for rare autosomal recessive disorders caused by mutations in proteins that interact with X chromosome-linked gene products may display predictable deviation from 1:1.

  3. Human adipose-derived stem cell transplantation as a potential therapy for collagen VI-related congenital muscular dystrophy

    PubMed Central

    2014-01-01

    Introduction Congenital muscular dystrophies (CMD) are a clinically and genetically heterogeneous group of neuromuscular disorders characterized by muscle weakness within the first two years of life. Collagen VI-related muscle disorders have recently emerged as one of the most common types of CMD. COL6 CMD is caused by deficiency and/or dysfunction of extracellular matrix (ECM) protein collagen VI. Currently, there is no specific treatment for this disabling and life-threatening disease. The primary cellular targets for collagen VI CMD therapy are fibroblasts in muscle, tendon and skin, as opposed to muscle cells for other types of muscular dystrophies. However, recent advances in stem cell research have raised the possibility that use of adult stem cells may provide dramatic new therapies for treatment of COL6 CMD. Methods Here, we developed a procedure for isolation of human stem cells from the adipose layer of neonatal skin. The adipose-derived stem cells (ADSC) were examined for expression of ECM and related genes using gene expression array analysis. The therapeutic potential of ADSC was assessed after a single intramuscular transplantation in collagen VI-deficient mice. Results Analysis of primary cultures confirmed that established ADSC represent a morphologically homogenous population with phenotypic and functional features of adult mesenchymal stem cells. A comprehensive gene expression analysis showed that ADSC express a vast array of ECM genes. Importantly, it was observed that ADSC synthesize and secrete all three collagen VI chains, suggesting suitability of ADSC for COL6 CMD treatment. Furthermore, we have found that a single intramuscular transplantation of ADSC into Col6a1−/−Rag1−/− mice under physiological and cardiotoxin-induced injury/regeneration conditions results in efficient engraftment and migration of stem cells within the skeletal muscle. Importantly, we showed that ADSC can survive long-term and continuously secrete the

  4. Intrinsic laryngeal muscles are spared from degeneration in the dy3K/dy3K mouse model of congenital muscular dystrophy type 1A.

    PubMed

    Häger, Mattias; Durbeej, Madeleine

    2009-01-01

    Deficiency of laminin alpha2 chain leads to a severe form of congenital muscular dystrophy (MDC1A). Here, we analyzed whether the intrinsic laryngeal muscles (ILM) are spared in the dy(3K)/dy(3K) mouse model of complete laminin alpha2 chain absence. No muscle degeneration was evident; expression of various laminin chains was similar to that of limb muscles, and sustained integrin alpha7B expression was noted in laminin alpha2 chain-deficient ILM. We conclude that ILM are spared in MDC1A.

  5. Molecular and Genetic Studies of Congenital Myopathies

    ClinicalTrials.gov

    2015-10-26

    Central Core Disease; Centronuclear Myopathy; Congenital Fiber Type Disproportion; Multiminicore Disease; Myotubular Myopathy; Nemaline Myopathy; Rigid Spine Muscular Dystrophy; Undefined Congenital Myopathy

  6. Alternative splicing and muscular dystrophy

    PubMed Central

    Pistoni, Mariaelena; Ghigna, Claudia; Gabellini, Davide

    2013-01-01

    Alternative splicing of pre-mRNAs is a major contributor to proteomic diversity and to the control of gene expression in higher eukaryotic cells. For this reasons, alternative splicing is tightly regulated in different tissues and developmental stages and its disruption can lead to a wide range of human disorders. The aim of this review is to focus on the relevance of alternative splicing for muscle function and muscle disease. We begin by giving a brief overview of alternative splicing, muscle-specific gene expression and muscular dystrophy. Next, to illustrate these concepts we focus on two muscular dystrophy, myotonic muscular dystrophy and facioscapulohumeral muscular dystrophy, both associated to disruption of splicing regulation in muscle. PMID:20603608

  7. Results of a two-year pilot study of clinical outcome measures in collagen VI- and laminin alpha2-related congenital muscular dystrophies.

    PubMed

    Meilleur, Katherine G; Jain, Minal S; Hynan, Linda S; Shieh, Ching-Yi; Kim, Eunice; Waite, Melissa; McGuire, Michelle; Fiorini, Courtney; Glanzman, Allan M; Main, Marion; Rose, Kristy; Duong, Tina; Bendixen, Roxanna; Linton, Melody M; Arveson, Irene C; Nichols, Carmel; Yang, Kelly; Fischbeck, Kenneth H; Wagner, Kathryn R; North, Kathryn; Mankodi, Ami; Grunseich, Christopher; Hartnett, Elizabeth J; Smith, Michaele; Donkervoort, Sandra; Schindler, Alice; Kokkinis, Angela; Leach, Meganne; Foley, A Reghan; Collins, James; Muntoni, Francesco; Rutkowski, Anne; Bönnemann, Carsten G

    2015-01-01

    Potential therapies are currently under development for two congenital muscular dystrophy (CMD) subtypes: collagen VI-related muscular dystrophy (COL6-RD) and laminin alpha 2-related dystrophy (LAMA2-RD). However, appropriate clinical outcome measures to be used in clinical trials have not been validated in CMDs. We conducted a two-year pilot study to evaluate feasibility, reliability, and validity of various outcome measures, particularly the Motor Function Measure 32, in 33 subjects with COL6-RD and LAMA2-RD. In the first year, outcome measures tested included: Motor Function Measure 32 (MFM32), forced vital capacity (FVC) percent predicted sitting, myometry, goniometry, 10-meter walk, Egen Klassification 2, and PedsQL(TM) Generic and Neuromuscular Cores. In the second year, we added the North Star Ambulatory Assessment (NSAA), Hammersmith Functional Motor Scale (HFMS), timed functional tests, Measure of Activity Limitations (ACTIVLIM), Quality of Upper Extremity Skills Test (QUEST), and Patient-Reported Outcomes Measurement Information System (PROMIS) fatigue subscale. The MFM32 showed strong inter-rater (0.92) and internal consistency (0.96) reliabilities. Concurrent validity for the MFM32 was supported by large correlations (range 0.623-0.936) with the following: FVC, NSAA, HFMS, timed functional tests, ACTIVLIM, and QUEST. Significant correlations of the MFM32 were also found with select myometry measurements, mainly of the proximal extremities and domains of the PedsQL(TM) scales focusing on physical health and neuromuscular disease. Goniometry measurements were less reliable. The Motor Function Measure is reliable and valid in the two specific subtypes of CMD evaluated, COL6-RD and LAMA2-RD. The NSAA is useful as a complementary outcome measure in ambulatory individuals. Preliminary concurrent validity of several other clinical outcome measures was also demonstrated for these subtypes. PMID:25307854

  8. Deficiency of syntrophin, dystroglycan, and merosin in a female infant with a congenital muscular dystrophy phenotype lacking cysteine-rich and C-terminal domains of dystrophin.

    PubMed

    Tachi, N; Ohya, K; Chiba, S; Matsuo, M; Patria, S Y; Matsumura, K

    1997-08-01

    Primary deficiency of merosin is the cause of the classic form of congenital muscular dystrophy (CMD) accompanied by brain white matter abnormalities. We report a female infant with dystrophinopathy who was deficient in merosin in skeletal muscle. The patient had a phenotype of typical CMD and white matter abnormalities on brain MRI. Merosin was greatly reduced in the biopsied skeletal muscle. However, the expression of dystroglycan and syntrophin was also greatly reduced, and the immunoreactivity for the antibodies against the cysteine-rich/C-terminal domains of dystrophin was absent in the sarcolemma. Reverse transcriptase polymerase chain reaction analysis of the dystrophin gene revealed a complete lack of exons 71 through 74. In skeletal muscle, only the mutant gene was expressed. These results suggest that the patient is a symptomatic Duchenne muscular dystrophy carrier with skewed X-inactivation. This patient illustrates for the first time that a dystrophin abnormality can cause a secondary deficiency of merosin in dystrophinopathy. The reduction of merosin may account for the clinical phenotype of CMD and correlate with the white matter abnormalities in our patient.

  9. Duchenne muscular dystrophy

    MedlinePlus

    Pseudohypertrophic muscular dystrophy; Muscular dystrophy - Duchenne type ... Duchenne muscular dystrophy is a form of muscular dystrophy . It worsens quickly. Other muscular dystrophies (including Becker's muscular dystrophy ) get ...

  10. A Novel Missense Mutation in POMT1 Modulates the Severe Congenital Muscular Dystrophy Phenotype Associated with POMT1 Nonsense Mutations

    PubMed Central

    Wallace, Stephanie E.; Conta, Jessie H.; Winder, Thomas L.; Willer, Tobias; Eskuri, Jamie M.; Haas, Richard; Patterson, Kathleen; Campbell, Kevin P.; Moore, Steven A.; Gospe, Sidney M.

    2014-01-01

    Mutations in POMT1 lead to a group of neuromuscular conditions ranging in severity from Walker-Warburg syndrome to limb girdle muscular dystrophy. We report two male siblings, ages 19 and 14, and an unrelated 6-year old female with early onset muscular dystrophy and intellectual disability with minimal structural brain anomalies and no ocular abnormalities. Compound heterozygous mutations in POMT1 were identified including a previously reported nonsense mutation (c.2167dupG; p.Asp723Glyfs*8) associated with Walker-Warburg syndrome and a novel missense mutation in a highly conserved region of the protein O-mannosyltransferase 1 protein (c.1958C>T; p.Pro653Leu). This novel variant reduces the phenotypic severity compared to patients with homozygous c.2167dupG mutations or compound heterozygous patients with a c.2167dupG mutation and a wide range of other mutant POMT1 alleles. PMID:24491487

  11. Angiotensin II type 1 receptor antagonists alleviate muscle pathology in the mouse model for laminin-α2-deficient congenital muscular dystrophy (MDC1A)

    PubMed Central

    2012-01-01

    Background Laminin-α2-deficient congenital muscular dystrophy (MDC1A) is a severe muscle-wasting disease for which no curative treatment is available. Antagonists of the angiotensin II receptor type 1 (AT1), including the anti-hypertensive drug losartan, have been shown to block also the profibrotic action of transforming growth factor (TGF)-β and thereby ameliorate disease progression in mouse models of Marfan syndrome. Because fibrosis and failure of muscle regeneration are the main reasons for the severe disease course of MDC1A, we tested whether L-158809, an analog derivative of losartan, could ameliorate the dystrophy in dyW/dyW mice, the best-characterized model of MDC1A. Methods L-158809 was given in food to dyW/dyW mice at the age of 3 weeks, and the mice were analyzed at the age of 6 to 7 weeks. We examined the effect of L-158809 on muscle histology and on muscle regeneration after injury as well as the locomotor activity and muscle strength of the mice. Results We found that TGF-β signaling in the muscles of the dyW/dyW mice was strongly increased, and that L-158809 treatment suppressed this signaling. Consequently, L-158809 reduced fibrosis and inflammation in skeletal muscle of dyW/dyW mice, and largely restored muscle regeneration after toxin-induced injury. Mice showed improvement in their locomotor activity and grip strength, and their body weight was significantly increased. Conclusion These data provide evidence that AT1 antagonists ameliorate several hallmarks of MDC1A in dyW/dyW mice, the best-characterized mouse model for this disease. Because AT1 antagonists are well tolerated in humans and widely used in clinical practice, these results suggest that losartan may offer a potential future treatment of patients with MDC1A. PMID:22943509

  12. Magnetic Resonance Imaging Is Sensitive to Pathological Amelioration in a Model for Laminin-Deficient Congenital Muscular Dystrophy (MDC1A)

    PubMed Central

    Vohra, Ravneet; Accorsi, Anthony; Kumar, Ajay; Walter, Glenn; Girgenrath, Mahasweta

    2015-01-01

    Purpose To elucidate the reliability of MRI as a non-invasive tool for assessing in vivo muscle health and pathological amelioration in response to Losartan (Angiotensin II Type 1 receptor blocker) in DyW mice (mouse model for Laminin-deficient Congenital Muscular Dystrophy Type 1A). Methods Multiparametric MR quantifications along with histological/biochemical analyses were utilized to measure muscle volume and composition in untreated and Losartan-treated 7-week old DyW mice. Results MRI shows that DyW mice have significantly less hind limb muscle volume and areas of hyperintensity that are absent in WT muscle. DyW mice also have significantly elevated muscle levels (suggestive of inflammation and edema). Muscle T2 returned to WT levels in response to Losartan treatment. When considering only muscle pixels without T2 elevation, DyW T2 levels are significantly lower than WT (suggestive of fibrosis) whereas Losartan-treated animals do not demonstrate this decrease in muscle T2. MRI measurements suggestive of elevated inflammation and fibrosis corroborate with increased Mac-1 positive cells as well as increased Picrosirius red staining/COL1a gene expression that is returned to WT levels in response to Losartan. Conclusions MRI is sensitive to and tightly corresponds with pathological changes in DyW mice and thus is a viable and effective non-invasive tool for assessing pathological changes. PMID:26379183

  13. Substitution of a conserved cysteine-996 in a cysteine-rich motif of the laminin {alpha}2-chain in congenital muscular dystrophy with partial deficiency of the protein

    SciTech Connect

    Nissinen, M.; Xu Zhang; Tryggvason, K.

    1996-06-01

    Congenital muscular dystrophies (CMDs) are autosomal recessive muscle disorders of early onset. Approximately half of CMD patients present laminin {alpha}2-chain (merosin) deficiency in muscle biopsies, and the disease locus has been mapped to the region of the LAMA2 gene (6q22-23) in several families. Recently, two nonsense mutations in the laminin {alpha}2-chain gene were identified in CMD patients exhibiting complete deficiency of the laminin {alpha}2-chain in muscle biopsies. However, a subset of CMD patients with linkage to LAMA2 show only partial absence of the laminin {alpha}2-chain around muscle fibers, by immunocytochemical analysis. In the present study we have identified a homozygous missense mutation in the {alpha}2-chain gene of a consanguineous Turkish family with partial laminin {alpha}2-chain deficiency. The T{r_arrow}C transition at position 3035 in the cDNA sequence results in a Cys996{r_arrow}Arg substitution. The mutation that affects one of the conserved cysteine-rich repeats in the short arm of the laminin {alpha}2-chain should result in normal synthesis of the chain and in formation and secretion of a heterotrimeric laminin molecule. Muscular dysfunction is possibly caused either by abnormal disulfide cross-links and folding of the laminin repeat, leading to the disturbance of an as yet unknown binding function of the laminin {alpha}2-chain and to shorter half-life of the muscle-specific laminin-2 and laminin-4 isoforms, or by increased proteolytic sensitivity, leading to truncation of the short arm. 42 refs., 7 figs.

  14. Emerging strategies for cell and gene therapy of the muscular dystrophies

    PubMed Central

    Muir, Lindsey A.; Chamberlain, Jeffrey S.

    2016-01-01

    The muscular dystrophies are a heterogeneous group of over 40 disorders that are characterised by muscle weakness and wasting. The most common are Duchenne muscular dystrophy and Becker muscular dystrophy, which result from mutations within the gene encoding dystrophin; myotonic dystrophy type 1, which results from an expanded trinucleotide repeat in the myotonic dystrophy protein kinase gene; and facioscapulohumeral dystrophy, which is associated with contractions in the subtelomeric region of human chromosome 1. Currently the only treatments involve clinical management of symptoms, although several promising experimental strategies are emerging. These include gene therapy using adeno-associated viral, lentiviral and adenoviral vectors and nonviral vectors, such as plasmid DNA. Exon-skipping and cell-based therapies have also shown promise in the effective treatment and regeneration of dystrophic muscle. The availability of numerous animal models for Duchenne muscular dystrophy has enabled extensive testing of a wide range of therapeutic approaches for this type of disorder. Consequently, we focus here on the therapeutic developments for Duchenne muscular dystrophy as a model of the types of approaches being considered for various types of dystrophy. We discuss the advantages and limitations of each therapeutic strategy, as well as prospects and recent successes in the context of future clinical applications. PMID:19555515

  15. Muscular dystrophy

    MedlinePlus

    ... this page: //medlineplus.gov/ency/article/001190.htm Muscular dystrophy To use the sharing features on this page, please enable JavaScript. Muscular dystrophy is a group of inherited disorders that cause ...

  16. Muscular Dystrophy

    MedlinePlus

    Muscular dystrophy (MD) is a group of more than 30 inherited diseases. They all cause muscle weakness and ... ability to walk. There is no cure for muscular dystrophy. Treatments can help with the symptoms and prevent ...

  17. Erythrocytes in muscular dystrophy. Investigation with /sup 31/P nuclear magnetic resonance spectroscopy

    SciTech Connect

    Sarpel, G.; Lubansky, H.J.; Danon, M.J.; Omachi, A.

    1981-05-01

    Phosphorus 31 nuclear magnetic resonance (/sup 31/P NMR) signals were recorded from intact human erythrocytes for 16 hours. Total phosphate concentration, which was estimated as the sum of the individual /sup 31/P signals, was 25% lower in erythrocytes from men with myotonic dystrophy than in control erythrocytes. The inorganic-phosphate fraction contained the highest average phosphate concentration over the 16-hour period, and made the major contribution to the difference in total phosphate between the two groups. This result was not observed in erythrocytes from either women with myotonic dystrophy or patients with Duchenne's dystrophy and may be due to a change in cell membrane permeability to inorganic phosphate, which leads to lower steady-state concentrations of the intracellular phosphates.

  18. Erythrocytes in muscular dystrophy. Investigation with 31P nuclear magnetic resonance spectroscopy

    SciTech Connect

    Sarpel, G.; Lubansky, H.J.; Danon, M.J.; Omachi, A.

    1981-05-01

    Phosphorus 31 nuclear magnetic resonance (31P NMR) signals were recorded from intact human erythrocytes for 16 hours. Total phosphate concentration, which was estimated as the sum of the individual 31P signals, was 25% lower in erythrocytes from men with myotonic dystrophy than in control erythrocytes. The inorganic-phosphate fraction contained the highest average phosphate concentration over the 16-hour period, and made the major contribution to the difference in total phosphate between the two groups. This result was not observed in erythrocytes from either women with myotonic dystrophy or patients with Duchenne's dystrophy and may be due to a change in cell membrane permeability to inorganic phosphate, which lead to lower steady-state concentrations of the intracellular phosphates.

  19. Muscular Dystrophies at Different Ages: Metabolic and Endocrine Alterations

    PubMed Central

    Cruz Guzmán, Oriana del Rocío; Chávez García, Ana Laura; Rodríguez-Cruz, Maricela

    2012-01-01

    Common metabolic and endocrine alterations exist across a wide range of muscular dystrophies. Skeletal muscle plays an important role in glucose metabolism and is a major participant in different signaling pathways. Therefore, its damage may lead to different metabolic disruptions. Two of the most important metabolic alterations in muscular dystrophies may be insulin resistance and obesity. However, only insulin resistance has been demonstrated in myotonic dystrophy. In addition, endocrine disturbances such as hypogonadism, low levels of testosterone, and growth hormone have been reported. This eventually will result in consequences such as growth failure and delayed puberty in the case of childhood dystrophies. Other consequences may be reduced male fertility, reduced spermatogenesis, and oligospermia, both in childhood as well as in adult muscular dystrophies. These facts all suggest that there is a need for better comprehension of metabolic and endocrine implications for muscular dystrophies with the purpose of developing improved clinical treatments and/or improvements in the quality of life of patients with dystrophy. Therefore, the aim of this paper is to describe the current knowledge about of metabolic and endocrine alterations in diverse types of dystrophinopathies, which will be divided into two groups: childhood and adult dystrophies which have different age of onset. PMID:22701119

  20. MR spectroscopy and diffusion tensor imaging of the brain in congenital muscular dystrophy with merosin deficiency: metabolite level decreases, fractional anisotropy decreases, and apparent diffusion coefficient increases in the white matter.

    PubMed

    Sijens, P E; Fock, J M; Meiners, L C; Potze, J H; Irwan, R; Oudkerk, M

    2007-06-01

    Brain magnetic resonance spectroscopy (MRS) and diffusion tensor imaging (DTI) in one patient with merosin-deficient congenital muscular dystrophy (MDCMD) revealed significant metabolite (choline, creatine, N-acetyl aspartate) level reductions, fractional anisotropy (FA) reduction and increased apparent diffusion coefficient (ADC) in the white matter (p<0.01, all). In the gray matter, the MRS properties did not differ significantly from those in controls. The ADC and FA, however, differed significantly as in the white matter, although the differences were less pronounced. This is the first quantitative MR study of the brain in a patient with MDCMD, which revealed that the concentrations of all MRS measured metabolites were decreased only in the white matter. This observation, combined with the DTI observed ADC increases and FA decrease, indicated a presence of vasogenic edema in the white matter.

  1. The molecular genetics of the corneal dystrophies--current status.

    PubMed

    Klintworth, Gordon K

    2003-05-01

    The pertinent literature on inherited corneal diseases is reviewed in terms of the chromosomal localization and identification of the responsible genes. Disorders affecting the cornea have been mapped to human chromosome 1 (central crystalline corneal dystrophy, familial subepithelial corneal amyloidosis, early onset Fuchs dystrophy, posterior polymorphous corneal dystrophy), chromosome 4 (Bietti marginal crystalline dystrophy), chromosome 5 (lattice dystrophy types 1 and IIIA, granular corneal dystrophy types 1, 2 and 3, Thiel-Behnke corneal dystrophy), chromosome 9 (lattice dystrophy type II), chromosome 10 (Thiel-Behnke corneal dystrophy), chromosome 12 (Meesmann dystrophy), chromosome 16 (macular corneal dystrophy, fish eye disease, LCAT disease, tyrosinemia type II), chromosome 17 (Meesmann dystrophy, Stocker-Holt dystrophy), chromosome 20 (congenital hereditary endothelial corneal dystrophy types I and II, posterior polymorphous corneal dystrophy), chromosome 21 (autosomal dominant keratoconus) and the X chromosome (cornea verticillata, cornea farinata, deep filiform corneal dystrophy, keratosis follicularis spinulosa decalvans, Lisch corneal dystrophy). Mutations in nine genes (ARSC1, CHST6, COL8A2, GLA, GSN, KRT3, KRT12, M1S1and TGFBI [BIGH3]) account for some of the corneal diseases and three of them are associated with amyloid deposition in the cornea (GSN, M1S1, TGFBI) including most of the lattice corneal dystrophies (LCDs) [LCD types I, IA, II, IIIA, IIIB, IV, V, VI and VII] recognized by their lattice pattern of linear opacities. Genetic studies on inherited diseases affecting the cornea have provided insight into some of these disorders at a basic molecular level and it has become recognized that distinct clinicopathologic phenotypes can result from specific mutations in a particular gene, as well as some different mutations in the same gene. A molecular genetic understanding of inherited corneal diseases is leading to a better appreciation of the

  2. Meaning of Muscular Dystrophy

    MedlinePlus

    ... Help White House Lunch Recipes The Meaning of Muscular Dystrophy KidsHealth > For Kids > The Meaning of Muscular Dystrophy ... you know someone who has MD. What Is Muscular Dystrophy? Muscular dystrophy (say: MUS-kyoo-lur DIS-troh- ...

  3. Corneal dystrophies

    PubMed Central

    Klintworth, Gordon K

    2009-01-01

    The term corneal dystrophy embraces a heterogenous group of bilateral genetically determined non-inflammatory corneal diseases that are restricted to the cornea. The designation is imprecise but remains in vogue because of its clinical value. Clinically, the corneal dystrophies can be divided into three groups based on the sole or predominant anatomical location of the abnormalities. Some affect primarily the corneal epithelium and its basement membrane or Bowman layer and the superficial corneal stroma (anterior corneal dystrophies), the corneal stroma (stromal corneal dystrophies), or Descemet membrane and the corneal endothelium (posterior corneal dystrophies). Most corneal dystrophies have no systemic manifestations and present with variable shaped corneal opacities in a clear or cloudy cornea and they affect visual acuity to different degrees. Corneal dystrophies may have a simple autosomal dominant, autosomal recessive or X-linked recessive Mendelian mode of inheritance. Different corneal dystrophies are caused by mutations in the CHST6, KRT3, KRT12, PIP5K3, SLC4A11, TACSTD2, TGFBI, and UBIAD1 genes. Knowledge about the responsible genetic mutations responsible for these disorders has led to a better understanding of their basic defect and to molecular tests for their precise diagnosis. Genes for other corneal dystrophies have been mapped to specific chromosomal loci, but have not yet been identified. As clinical manifestations widely vary with the different entities, corneal dystrophies should be suspected when corneal transparency is lost or corneal opacities occur spontaneously, particularly in both corneas, and especially in the presence of a positive family history or in the offspring of consanguineous parents. Main differential diagnoses include various causes of monoclonal gammopathy, lecithin-cholesterol-acyltransferase deficiency, Fabry disease, cystinosis, tyrosine transaminase deficiency, systemic lysosomal storage diseases (mucopolysaccharidoses

  4. Muscular dystrophy in a dog resembling human becker muscular dystrophy.

    PubMed

    Baroncelli, A B; Abellonio, F; Pagano, T B; Esposito, I; Peirone, B; Papparella, S; Paciello, O

    2014-05-01

    A 3-year-old, male Labrador retriever dog was presented with clinical signs of progressive exercise intolerance, bilateral elbow extension, rigidity of the forelimbs, hindlimb flexion and kyphosis. Microscopical examination of muscle tissue showed marked variability in myofibre size, replacement of muscle with mature adipose tissue and degeneration/regeneration of muscle fibres, consistent with muscular dystrophy. Immunohistochemical examination for dystrophin showed markedly reduced labelling with monoclonal antibodies specific for the rod domain and the carboxy-terminal of dystrophin, while expression of β-sarcoglycan, γ-sarcoglycan and β-dystroglycan was normal. Immunoblotting revealed a truncated dystrophin protein of approximately 135 kDa. These findings supported a diagnosis of congenital canine muscular dystrophy resembling Becker muscular dystrophy in man.

  5. Muscular Dystrophy

    MedlinePlus

    ... be affected. Limb-girdle muscular dystrophy (LGMD) affects boys and girls equally, weakening muscles in the shoulders and upper ... weakness and poor muscle tone. Occurring in both girls and boys, it can have different symptoms. It varies in ...

  6. Hypotrichosis with juvenile macular dystrophy: Portuguese case.

    PubMed

    Elfatoiki, Fatima Zahra; Cordoliani, Florance; Pascal Regane, Pascal; Afforitit-Demoge, Aude

    2016-01-01

    Hypotrichosis with juvenile macular dystrophy is a rare congenital disease mainly found in the Druze population of Northern Israel. This disorder is caused by the CDH3 mutation encoding P-cadherin, which is expressed in retinal pigment epithelium and hair follicles. An 11-year-old girl who was born to related Portuguese parents, had hypotrichosis since birth and macular dystrophy diagnosed at age 5. Fundus examination and fluorescein angiography revealed located macular pigmentary abnormalities. No molecular analysis was done. A fundus examination should be considered mandatory in the assessment of congenital hypotrichosis. PMID:27617529

  7. The Myotonic Plot Thickens: Electrical Myotonia in Antimuscle-Specific Kinase Myasthenia Gravis

    PubMed Central

    Magnussen, Marcus; Karakis, Ioannis; Harrison, Taylor B.

    2015-01-01

    Electrical myotonia is known to occur in a number of inherited and acquired disorders including myotonic dystrophies, channelopathies, and metabolic, toxic, and inflammatory myopathies. Yet, electrical myotonia in myasthenia gravis associated with antibodies against muscle-specific tyrosine kinase (MuSK) has not been previously reported. We describe two such patients, both of whom had a typical presentation of proximal muscle weakness with respiratory failure in the context of a significant electrodecrement in repetitive nerve stimulation. In both cases, concentric needle examination revealed electrical myotonia combined with myopathic motor unit morphology and early recruitment. These findings suggest that MuSK myasthenia should be included within the differential diagnosis of disorders with electrical myotonia. PMID:26770848

  8. Immunohistochemical Characterization of Facioscapulohumeral Muscular Dystrophy Muscle Biopsies

    PubMed Central

    Statland, Jeffrey M; Odrzywolski, Karen J; Shah, Bharati; Henderson, Don; Fricke, Alex F.; van der Maarel, Silvère M; Tapscott, Stephen J; Tawil, Rabi

    2015-01-01

    Background Posited pathological mechanisms in Facioscapulohumeral Muscular Dystrophy (FSHD) include activation in somatic tissue of normally silenced genes, increased susceptibility to oxidative stress, and induction of apoptosis. Objective To determine the histopathological changes in FSHD muscle biopsies and compare to possible pathological mechanisms of disease. Methods We performed a cross-sectional study on quadriceps muscle biopsies from 32 genetically confirmed FSHD participants, compared to healthy volunteers and myotonic dystrophy type 1 as disease controls. Biopsies were divided into groups to evaluate apoptosis rates, capillary density, myonuclear and satellite cell counts. Results Apoptosis rates were increased in FSHD (n=10, 0.74%) compared to myotonic dystrophy type 1 (n=10, 0.14%, P=0.003) and healthy volunteers (n=14, 0.13%, P=0.002). Apoptosis was higher in FSHD patients with the smallest residual D4Z4 fragments. Capillary density was decreased in FSHD1 (n=10, 316 capillaries/mm2) compared to healthy volunteers (n=15, 448 capillaries/mm2, P=0.001). No differences were seen in myonuclear or satellite cell counts. Conclusions Preliminary evidence for increased apoptosis rates and reduced capillary density may reflect histopathological correlates of disease activity in FSHD. The molecular-pathological correlates to these changes warrants further investigation. PMID:26345300

  9. [Genetic diagnostic testing in inherited retinal dystrophies].

    PubMed

    Kohl, S; Biskup, S

    2013-03-01

    Inherited retinal dystrophies are clinically and genetically highly heterogeneous. They can be divided according to the clinical phenotype and course of the disease, as well as the underlying mode of inheritance. Isolated retinal dystrophies (i.e., retinitis pigmentosa, Leber's congenital amaurosis, cone and cone-rod dystrophy, macular dystrophy, achromatopsia, congenital stationary nightblindness) and syndromal forms (i.e., Usher syndrome, Bardet-Biedl syndrome) can be differentiated. To date almost 180 genes and thousands of distinct mutations have been identified that are responsible for the different forms of these blinding illnesses. Until recently, there was no adequate diagnostic genetic testing available. With the development of the next generation sequencing technologies, a comprehensive genetic screening analysis for all known genes for inherited retinal dystrophies has been established at reasonable costs and in appropriate turn-around times. Depending on the primary clinical diagnosis and the presumed mode of inheritance, different diagnostic panels can be chosen for genetic testing. Statistics show that in 55-80 % of the cases the genetic defect of the inherited retinal dystrophy can be identified with this approach, depending on the initial clinical diagnosis. The aim of any genetic diagnostics is to define the genetic cause of a given illness within the affected patient and family and thereby i) confirm the clinical diagnosis, ii) provide targeted genetic testing in family members, iii) enable therapeutic intervention, iv) give a prognosis on disease course and progression and v) in the long run provide the basis for novel therapeutic approaches and personalised medicine.

  10. Facioscapulohumeral Dystrophy.

    PubMed

    Wang, Leo H; Tawil, Rabi

    2016-07-01

    Facioscapulohumeral muscular dystrophy (FSHD) is a clinically recognizable and relatively common muscular dystrophy. It is inherited mostly as an autosomal dominant disease or in a minority of cases, in a digenic pattern. The disease manifestation is variable and most likely dependent on genetic and epigenetic factors. We review the history, epidemiology, clinical presentation, and genetics of the disease, present the recently elucidated molecular pathogenesis, discuss the pathology and the possible consequence of the inflammation seen in the muscle biopsies, and consider future treatments. PMID:27215221

  11. Muscular dystrophy - resources

    MedlinePlus

    Resources - muscular dystrophy ... The following organizations are good resources for information on muscular dystrophy : Muscular Dystrophy Association -- www.mdausa.org National Institute of Neurological Disorders and Stroke -- www.ninds.nih. ...

  12. Developmental Defects in a Zebrafish Model for Muscular Dystrophies Associated with the Loss of Fukutin-Related Protein (FKRP)

    ERIC Educational Resources Information Center

    Thornhill, Paul; Bassett, David; Lochmuller, Hanns; Bushby, Kate; Straub, Volker

    2008-01-01

    A number of muscular dystrophies are associated with the defective glycosylation of [alpha]-dystroglycan and many are now known to result from mutations in a number of genes encoding putative or known glycosyltransferases. These diseases include severe forms of congenital muscular dystrophy (CMD) such as Fukuyama type congenital muscular dystrophy…

  13. Congenital Muscle Disease Study of Patient and Family Reported Medical Information

    ClinicalTrials.gov

    2016-07-27

    Muscular Dystrophy; Congenital Muscular Dystrophy; Fukutin-related Protein Gene; Limb Girdle; FKRP Gene; Childhood Onset LGMD; Adult Onset LGMD; POMT1; POMT2; POMGnT1; LARGE; Alpha Dystroglycan; Dystroglycanopathy; Centronuclear; Multiminicore; Multicore; Minicore; Congenital Fiber Type Disproportion; Myotubular; Nemaline; Congenital Myopathy; Neuromuscular; Rigid Spine; Phenotype-Genotype Correlation; Cough Assisted Device; Neuromuscular Disease; Respiratory Exacerbation; Invasive Ventilation; Chest Physiotherapy; Congenital Myopathies; Genetic Mutations; Hypertrophic Cardiomyopathy; Wheelchair Use; Cataract; Opthalmoplegia; Ullrich Congenital Muscular Dystrophy; Intermediate Collagen VI Myopathy; Laminin Alpha 2 Related Congenital Muscular Dystrophy; MDC1A; Merosin Deficient Congenital Muscular Dystrophy; Congenital Muscular Dystrophy Undiagnosed; Congenital Muscular Dystrophy Merosin Positive; Walker Warburg Syndrome; Muscle Eye Brain Disease; Fukuyama; Integrin Alpha 7 Deficiency; Integrin Alpha 9 Deficiency; Laminopathy; Lamin AC; SEPN 1 Related Myopathies; Bethlem Myopathy; Dystroglycanopathies; LGMD2K; LGMD2I; LGMD2L; LGMD2N; Actin Aggregation Myopathy; Cap Disease; Central Core Disease; Centronuclear Myopathy; Core Rod Myopathy; Hyaline Body Myopathy; Multiminicore Myopathy; Myotubular Myopathy; Nemaline Myopathy; Tubular Aggregate Myopathy; Zebra Body Disease Myopathy; Congenital Myopathy Other; Reducing Body Myopathy; Sarcotubular Myopathy; Spheroid Body Myopathy

  14. Genetics Home Reference: congenital stromal corneal dystrophy

    MedlinePlus

    ... of decorin. This abnormal protein interferes with the organization of collagen fibrils in the cornea. As poorly arranged collagen fibrils accumulate, the cornea becomes cloudy. These corneal changes lead to reduced visual acuity and related eye ...

  15. The cone dystrophies.

    PubMed

    Simunovic, M P; Moore, A T

    1998-01-01

    The cone dystrophies are a heterogeneous group of inherited disorders that result in dysfunction of the cone photoreceptors and sometimes their post-receptoral pathways. The major clinical features of cone dystrophy are photophobia, reduced visual acuity and abnormal colour vision. Ganzfeld electroretinography shows reduced or absent cone responses. On the basis of their natural history, the cone dystrophies may be broadly divided into two groups: stationary and progressive cone dystrophies. The stationary cone dystrophies have received more attention, and subsequently our knowledge of their molecular genetic, psychophysical and clinical characteristics is better developed. Various methods of classification have been proposed for the progressive cone dystrophies, but none is entirely satisfactory, largely because the underlying disease mechanisms are poorly understood. Multidisciplinary studies involving clinical assessment, molecular genetics, electrophysiology and psychophysics should lead to an improved understanding of the pathogenesis of these disorders.

  16. Different types of fatigue in patients with facioscapulohumeral dystrophy, myotonic dystrophy and HMSN-I. Experienced fatigue and physiological fatigue.

    PubMed

    Kalkman, Joke S; Zwarts, Machiel J; Schillings, Maartje L; van Engelen, Baziel G M; Bleijenberg, Gijs

    2008-09-01

    Although fatigue is a common symptom in neuromuscular disorders, little is known about different types of fatigue. Sixty-five FSHD, 79 adult-onset MD and 73 HMSN type I patients were studied. Experienced fatigue was assessed with the CIS-fatigue subscale. Physiological fatigue was measured during a 2-min sustained maximal voluntary contraction of the biceps brachii muscle using the twitch interpolation technique to assess central activation failure (CAF) and peripheral fatigue. Experienced fatigue, CAF and peripheral fatigue appeared to be predominantly separate types of fatigue. PMID:18690504

  17. Congenital Hypothyroidism

    MedlinePlus

    ... Body in Balance › Congenital Hypothyroidism Fact Sheet Congenital Hypothyroidism March, 2012 Download PDFs English Espanol Editors Rosalind S. ... MD Susan R. Rose, MD What is congenital hypothyroidism? Newborn babies who are unable to make enough ...

  18. [A descriptive study of the neuropsychological and psychopathological profile in patients with type 1 myotonic dystrophy].

    PubMed

    Seijas-Gomez, Raquel; Basterra-Jimenez, Izaskun; Luna-Lario, Pilar; Tirapu-Ustarroz, Javier; Cabada-Giadas, Teresa; Iridoy-Zulet, Marina; Jerico-Pascual, Ivonne; Gargallo-Vaamonde, Álvaro; Lopez-Goni, José Javier

    2015-12-16

    Introduccion. La distrofia miotonica tipo 1 (DM-1) o enfermedad de Steinert es un trastorno multisistemico y progresivo. Se han encontrado deficits cognitivos, clinica depresiva y alta incidencia de rasgos de personalidad ansiosos con afectacion tanto en la funcionalidad como en la calidad de vida de estos pacientes. Objetivo. Describir el perfil cognitivo y psicopatologico de una muestra de pacientes con la variante adulta de DM-1. Pacientes y metodos. Se selecciono una muestra de 27 pacientes con diagnostico de DM-1 en seguimiento en el Servicio de Neurologia del Complejo Hospitalario de Navarra. Los criterios de inclusion fueron tener menos de 50 anos y descartar cualquier otra patologia o condicion fisica que impidiese realizar la evaluacion psicologica. Se utilizo una bateria de evaluacion neuropsicologica especificamente disenada para este tipo de patologia, ademas de medidas de psicopatologia y funcionalidad. Resultados. La evaluacion neuropsicologica reflejo, principalmente, deficits en habilidades visuoconstructivas, visuoespaciales, atencion alternante y en sintomatologia disejecutiva heteroinformada. El grupo de pacientes no presento sintomatologia depresiva ni ansiosa clinicamente significativa, pero si puntuaciones elevadas en obsesion-compulsion, sensibilidad interpersonal, ideacion paranoide y psicoticismo. Los resultados orientaron hacia un deterioro en la funcionalidad. Conclusiones. En el abordaje integral de la DM-1, la caracterizacion y el seguimiento evolutivo del perfil cognitivo, psicopatologico y de personalidad, asi como del nivel de funcionalidad, contribuyen a la mejora de la calidad de vida de estos pacientes.

  19. Pilomatrixoma of the breast in a patient with type 1 myotonic dystrophy: successful surgical approach.

    PubMed

    Fama', F; Ieni, A; Tchernev, G; Chokoeva, A A; Maximov, G K; Wollina, U; Lotti, T; Patterson, J W; Fioranelli, M; Roccia, M G; Guarneri, C; Gioffre-Florio, M

    2016-01-01

    Malherbe’s calcifying epithelioma is an uncommon cutaneous tumour that originates from the matrix cells of hair follicle. It was initially described by Malherbe as a benign calcifying epithelioma. Several ultra-structural and electron-microscopic studies later demonstrated its origin from matrix cells and the term pilomatrixoma was introduced. The treatment of this tumour remains mainly surgical. Malignant cases with post-surgical recurrences have been described in literature and recurrences have been related to an incomplete surgical treatment or tumour aggressiveness. We present the case of 31-year-old female patient with pilomatrixoma of the breast, which was very similar to fibroadenoma, in terms of size and other clinical features. We successfully treated this patient surgically, and the aesthetic results were good, despite the proximity of the tumour to the areola-nipple complex. Fifteen months later, the patient is doing well, free of any clinical local recurrence. PMID:27373126

  20. An empiric comparison of linkage disequilibrium parameters in disease gene localizations; the myotonic dystrophy experience

    SciTech Connect

    Podolsky, L.; Baird, S.; Korneluk, R.G.

    1994-09-01

    Analyses of linkage disequilibrium (LD) between markers of known location and disease phenotypes often provide valuable information in efforts to clone the causative genes. However, there exist a number of factors which may attenuate a consistent inverse relationship between physical distance and LD for a given pairing of a genetic marker and a human disease gene. Chief among these is the effect of the general population frequency of an allele which demonstrates LD with a disease gene. Possibly as a result of this, a number of methods of calculating LD has been proposed. We have calculated seven such LD parameters for twelve physically mapped RFLP`s from a 1.3 Mb DM gene containing region of 19q13.3 using 107 DM and 213 non-DM chromosomes. Correlation of the DM-marker physical distance with LD for the 12 loci reveals the Yule coefficient and Dij{prime} parameter to give the most consistent relationship. The D{prime} parameter shown to have a relative allele frequency independence gave only a weak correlation. A similar analysis is being carried out on published cystic fibrosis genetic and physical mapping data. The parameters identified in this study may be the most appropriate for future LD based localizations of disease genes.

  1. Evaluation of Limb-Girdle Muscular Dystrophy

    ClinicalTrials.gov

    2014-03-06

    Becker Muscular Dystrophy; Limb-Girdle Muscular Dystrophy, Type 2A (Calpain-3 Deficiency); Limb-Girdle Muscular Dystrophy, Type 2B (Miyoshi Myopathy, Dysferlin Deficiency); Limb-Girdle Muscular Dystrophy, Type 2I (FKRP-deficiency)

  2. Embryological pigment epithelial dystrophies.

    PubMed

    François, J

    1976-01-01

    The embryological pigment epithelial dystrophies may be due, although rather rarely, to chemical factors, such as antibiotics and thalidomide, to ionizing radiation and to infectious factors, syphilis or viral infections, such as mumps, measles, varicella, or cytomegalovirus. The most frequent and the most typical dystrophy is, nevertheless, the rubella epitheliopathy with its widespread scattered black pigment deposits, found predominantly in the posterior pole, and its unaffected visual functions. The macular dystrophy associated with deaf-mutism is also often due to a maternal rubella infection.

  3. Bortezomib partially improves laminin α2 chain-deficient muscular dystrophy.

    PubMed

    Körner, Zandra; Fontes-Oliveira, Cibely C; Holmberg, Johan; Carmignac, Virginie; Durbeej, Madeleine

    2014-05-01

    Congenital muscular dystrophy, caused by mutations in LAMA2 (the gene encoding laminin α2 chain), is a severe and incapacitating disease for which no therapy is yet available. We have recently demonstrated that proteasome activity is increased in laminin α2 chain-deficient muscle and that treatment with the nonpharmaceutical proteasome inhibitor MG-132 reduces muscle pathology in laminin α2 chain-deficient dy(3K)/dy(3K) mice. Here, we explore the use of the selective and therapeutic proteasome inhibitor bortezomib (currently used for treatment of relapsed multiple myeloma and mantle cell lymphoma) in dy(3K)/dy(3K) mice and in congenital muscular dystrophy type 1A muscle cells. Outcome measures included quantitative muscle morphology, gene and miRNA expression analyses, proteasome activity, motor activity, and survival. Bortezomib improved several histological hallmarks of disease, partially normalized miRNA expression (miR-1 and miR-133a), and enhanced body weight, locomotion, and survival of dy(3K)/dy(3K) mice. In addition, bortezomib reduced proteasome activity in congenital muscular dystrophy type 1A myoblasts and myotubes. These findings provide evidence that the proteasome inhibitor bortezomib partially reduces laminin α2 chain-deficient muscular dystrophy. Investigation of the clinical efficacy of bortezomib administration in congenital muscular dystrophy type 1A clinical trials may be warranted.

  4. How Is Muscular Dystrophy Diagnosed?

    MedlinePlus

    ... Information Clinical Trials Resources and Publications How is muscular dystrophy diagnosed? Skip sharing on social media links Share this: Page Content The first step in diagnosing muscular dystrophy (MD) is a visit with a health care ...

  5. Occult Macular Dystrophy

    PubMed Central

    Sayman Muslubaş, Işıl; Arf, Serra; Hocaoğlu, Mümin; Özdemir, Hakan; Karaçorlu, Murat

    2016-01-01

    Occult macular dystrophy is an inherited macular dystrophy characterized by a progressive decline of bilateral visual acuity with normal fundus appearance, fluorescein angiogram and full-field electroretinogram. This case report presents a 20-year-old female patient with bilateral progressive decline of visual acuity for six years. Her visual acuity was 3-4/10 in both eyes. Anterior segment and fundus examination, fluorescein angiogram and full-field electroretinogram were normal. She could read all Ishihara pseudoisochromatic plates. Fundus autofluorescence imaging was normal. There was a mild central hyporeflectance on fundus infrared reflectance imaging in both eyes. Reduced foveal thickness and alterations of the photoreceptor inner and outer segment junction were observed by optical coherence tomography in both eyes. Central scotoma was also found by microperimetry and reduced central response was revealed by multifocal electroretinogram in both eyes. These findings are consistent with the clinical characteristics of occult macular dystrophy. PMID:27800268

  6. Continuous infusion propofol general anesthesia for dental treatment in patients with progressive muscular dystrophy.

    PubMed

    Kawaai, Hiroyoshi; Tanaka, Kazuho; Yamazaki, Shinya

    2005-01-01

    Progressive muscular dystrophy may produce abnormal reactions to several drugs. There is no consensus of opinion regarding the continuous infusion of propofol in patients with progressive muscular dystrophy. We successfully treated 2 patients with progressive muscular dystrophy who were anesthetized with a continuous infusion of propofol. In case 1, a 19-year-old, 59-kg man with Becker muscular dystrophy and mental retardation was scheduled for dental treatment under general anesthesia. General anesthesia was maintained by a continuous infusion of 6-10 mg/kg propofol per hour and an inhalational mixture of 67% nitrous oxide and 33% oxygen. No complications were observed during or after the operation. In case 2, a 5-year-old, 11-kg boy with Fukuyama type congenital muscular dystrophy and slight mental retardation was scheduled for dental treatment under general anesthesia. General anesthesia was maintained with a continuous infusion of 6-12 mg/kg propofol per hour and an inhalational mixture of 0.5-1.5% sevoflurane in 67% nitrous oxide and 33% oxygen. No complications were observed during or after the operation. It is speculated that a continuous infusion of propofol in progressive muscular dystrophy does not cause malignant hyperthermia because serum levels of creatine phosphokinase and myoglobin decreased after our anesthetic management. Furthermore, our observations suggest that sevoflurane may have some advantages in patients with progressive type muscular dystrophies other than Duchenne muscular dystrophy and Becker muscular dystrophy. In conclusion, our cases suggest that a continuous infusion of propofol for the patients with progressive muscular dystrophy is a safe component of our anesthetic strategy. PMID:15859443

  7. Congenital hemangiomas.

    PubMed

    Boull, Christina; Maguiness, Sheilagh M

    2016-09-01

    Congenital hemangiomas are rare solitary vascular tumors that do not proliferate after birth. They are characterized as either rapidly involuting congenital hemangiomas (RICHs) or noninvoluting congenital hemangiomas (NICHs) based on their clinical progression. NICHs have no associated complications, but are persistent. RICH, while usually asymptomatic, may ulcerate or bleed early in their presentation, but involute quickly during the first few months of life. Hepatic RICHs are not associated with cutaneous RICHs, but may result in high-output cardiac failure due to arteriovenous or portovenous shunting. In the following review, the clinical characteristics and current management specific to congenital hemangiomas is discussed.

  8. Congenital hemangiomas.

    PubMed

    Boull, Christina; Maguiness, Sheilagh M

    2016-03-01

    Congenital hemangiomas are rare solitary vascular tumors that do not proliferate after birth. They are characterized as either rapidly involuting congenital hemangiomas (RICHs) or noninvoluting congenital hemangiomas (NICHs) based on their clinical progression. NICHs have no associated complications, but are persistent. RICH, while usually asymptomatic, may ulcerate or bleed early in their presentation, but involute quickly during the first few months of life. Hepatic RICHs are not associated with cutaneous RICHs, but may result in high-output cardiac failure due to arteriovenous or portovenous shunting. In the following review, the clinical characteristics and current management specific to congenital hemangiomas is discussed. PMID:27607320

  9. Genetics Home Reference: tibial muscular dystrophy

    MedlinePlus

    ... Names for This Condition tardive tibial muscular dystrophy TMD Udd distal myopathy Udd-Markesbery muscular dystrophy Udd ... titin may cause more severe tibial muscular dystrophy (TMD). Neuromuscul Disord. 2008 Dec;18(12):922-8. ...

  10. Progressive cone dystrophy.

    PubMed Central

    Ripps, H; Noble, K G; Greenstein, V C; Siegel, I M; Carr, R E

    1987-01-01

    Psychophysical, reflectometric, and electrophysiological studies were performed on four members of a dominant pedigree with progressive cone dystrophy. The two youngest individuals were asymptomatic at the initial examination, and none of the subjects complained of problems associated with night vision. Absent or grossly reduced cone-mediated ERG responses revealed the widespread loss of cone function. Moderate elevations (1 log unit) in absolute threshold together with reductions in rhodopsin levels in the midperipheral retina provided evidence of a mild impairment of the rod system also, although not to the degree seen in a cone-rod dystrophy. The progressive nature of the disease was apparent from the case histories and the changes in visual performance that occurred on re-test after a 5-year interval. Likewise, the results of incremental threshold measurements at several retinal loci suggested that peripheral cones may be affected earlier and more severely than those in the central retina. PMID:3502298

  11. Facioscapulohumeral Muscular Dystrophy

    PubMed Central

    Statland, Jeffrey M.; Tawil, Rabi

    2014-01-01

    Facioscapulohumeral muscular dystrophy (FSHSD) is one of the most common adult muscular dystrophies and is divided into types 1 and 2 based on genetic mutation. Clinically both FSHD types 1 and 2 demonstrate often asymmetric and progressive muscle weakness affecting initially the face, shoulder, and arms, followed by the distal and then proximal lower extremities later in the disease course. Approximately 95% of patients, termed FSHD1, have a deletion of a key number of repetitive elements on chromosome 4q35. The remaining 5%, termed FSHD2, have no deletion on chromosome 4q35. Nevertheless, both FSHD types 1 and 2 share a common downstream mechanism making it possible that future disease-directed therapies will be effective for both FSHD types 1 and 2. PMID:25037087

  12. Sarcoglycans in muscular dystrophy.

    PubMed

    Hack, A A; Groh, M E; McNally, E M

    Muscular dystrophy is a heterogeneous genetic disease that affects skeletal and cardiac muscle. The genetic defects associated with muscular dystrophy include mutations in dystrophin and its associated glycoproteins, the sarcoglycans. Furthermore, defects in dystrophin have been shown to cause a disruption of the normal expression and localization of the sarcoglycan complex. Thus, abnormalities of sarcoglycan are a common molecular feature in a number of dystrophies. By combining biochemistry, molecular cell biology, and human and mouse genetics, a growing understanding of the sarcoglycan complex is emerging. Sarcoglycan appears to be an important, independent mediator of dystrophic pathology in both skeletal muscle and heart. The absence of sarcoglycan leads to alterations of membrane permeability and apoptosis, two shared features of a number of dystrophies. beta-sarcoglycan and delta-sarcoglycan may form the core of the sarcoglycan subcomplex with alpha- and gamma-sarcoglycan less tightly associated to this core. The relationship of epsilon-sarcoglycan to the dystrophin-glycoprotein complex remains unclear. Animals lacking alpha-, gamma- and delta-sarcoglycan have been described and provide excellent opportunities for further investigation of the function of sarcoglycan. Dystrophin with dystroglycan and laminin may be a mechanical link between the actin cytoskeleton and the extracellular matrix. By positioning itself in close proximity to dystrophin and dystroglycan, sarcoglycan may function to couple mechanical and chemical signals in striated muscle. Sarcoglycan may be an independent signaling or regulatory module whose position in the membrane is determined by dystrophin but whose function is carried out independent of the dystrophin-dystroglycan-laminin axis.

  13. Connective tissue growth factor is overexpressed in muscles of human muscular dystrophy.

    PubMed

    Sun, Guilian; Haginoya, Kazuhiro; Wu, Yanling; Chiba, Yoko; Nakanishi, Tohru; Onuma, Akira; Sato, Yuko; Takigawa, Masaharu; Iinuma, Kazuie; Tsuchiya, Shigeru

    2008-04-15

    The detailed process of how dystrophic muscles are replaced by fibrotic tissues is unknown. In the present study, the immunolocalization and mRNA expression of connective tissue growth factor (CTGF) in muscles from normal and dystrophic human muscles were examined with the goal of elucidating the pathophysiological function of CTGF in muscular dystrophy. Biopsies of frozen muscle from patients with Duchenne muscular dystrophy (DMD), Becker muscular dystrophy, congenital muscular dystrophy, spinal muscular atrophy, congenital myopathy were analyzed using anti-CTGF polyclonal antibody. Reverse transcription-polymerase chain reaction (RT-PCR) was also performed to evaluate the expression of CTGF mRNA in dystrophic muscles. In normal muscle, neuromuscular junctions and vessels were CTGF-immunopositive, which suggests a physiological role for CTGF in these sites. In dystrophic muscle, CTGF immunoreactivity was localized to muscle fiber basal lamina, regenerating fibers, and the interstitium. Triple immunolabeling revealed that activated fibroblasts were immunopositive for CTGF and transforming growth factor-beta1 (TGF-beta1). RT-PCR analysis revealed increased levels of CTGF mRNA in the muscles of DMD patients. Co-localization of TGF-beta1 and CTGF in activated fibroblasts suggests that CTGF expression is regulated by TGF-beta1 through a paracrine/autocrine mechanism. In conclusion, TGF-beta1-CTGF pathway may play a role in the fibrosis that is commonly observed in muscular dystrophy.

  14. Congenital Myopathy

    MedlinePlus

    ... arms and legs, droopy eyelids, and problems with eye movements. Weakness often gets worse with time. Central core ... difficulties occur as well. Some children have weakened eye movements. Congenital fiber-type disproportion myopathy is a rare ...

  15. Congenital syphilis

    MedlinePlus

    Congenital lues; Fetal syphilis ... which is passed from mother to child during fetal development or at birth. Nearly half of all ... Saunders; 2014:chap 143. Duff P. Maternal and fetal infections. In: Creasy RK, Resnik R, Iams JD, ...

  16. Congenital rubella

    MedlinePlus

    ... mother is infected with the virus that causes German measles. Congenital means the condition is present at ... Gershon AA. Rubella virus (German measles). In: Mandell GL, Bennett JE, ... of Infectious Diseases . 8th ed. Philadelphia, PA: Elsevier ...

  17. Congenital myopathies.

    PubMed

    Romero, Norma Beatriz; Clarke, Nigel F

    2013-01-01

    Congenital myopathies are a heterogeneous group of inherited muscle disorders, characterized by the predominance of particular histopathological features on muscle biopsy, such as cores (central core disease) or rods (nemaline myopathy). Clinically, early onset of the disease, stable or slowly progressive muscle weakness, hypotonia and delayed motor development are common in most forms. As a result, the diagnosis of a subtype of congenital myopathy is largely based on the presence of specific structural abnormalities in the skeletal muscle detected by enzyme-histochemistry and electron microscopy studies. During the last decades there have been significant advances in the identification of the genetic basis of most congenital myopathies. However, there is significant genetic heterogeneity within the main groups of congenital myopathies, and mutations in one particular gene may also cause diverse clinical and morphological phenotypes. Thus, the nosography and nosology in this field is still evolving. PMID:23622357

  18. [Congenital analgesia].

    PubMed

    Accornero, N; Bini, G; Cruccu, G

    1980-01-01

    The case of a 12 years old boy with a congenital anaesthesia covering all cutaneous and visceral districts is reported. There were no other neurological abnormalities apart a light mental retardation and loss of axon reflex after intradermal injection of hystamine. Notwithstanding this last finding a diagnosis of congenital indifference to pain was made. The differential diagnosis between indifference and insensitivity to pain is discussed. PMID:6162189

  19. Muscle diseases: the muscular dystrophies.

    PubMed

    McNally, Elizabeth M; Pytel, Peter

    2007-01-01

    Dystrophic muscle disease can occur at any age. Early- or childhood-onset muscular dystrophies may be associated with profound loss of muscle function, affecting ambulation, posture, and cardiac and respiratory function. Late-onset muscular dystrophies or myopathies may be mild and associated with slight weakness and an inability to increase muscle mass. The phenotype of muscular dystrophy is an endpoint that arises from a diverse set of genetic pathways. Genes associated with muscular dystrophies encode proteins of the plasma membrane and extracellular matrix, and the sarcomere and Z band, as well as nuclear membrane components. Because muscle has such distinctive structural and regenerative properties, many of the genes implicated in these disorders target pathways unique to muscle or more highly expressed in muscle. This chapter reviews the basic structural properties of muscle and genetic mechanisms that lead to myopathy and muscular dystrophies that affect all age groups.

  20. Cone rod dystrophies.

    PubMed

    Hamel, Christian P

    2007-01-01

    Cone rod dystrophies (CRDs) (prevalence 1/40,000) are inherited retinal dystrophies that belong to the group of pigmentary retinopathies. CRDs are characterized by retinal pigment deposits visible on fundus examination, predominantly localized to the macular region. In contrast to typical retinitis pigmentosa (RP), also called the rod cone dystrophies (RCDs) resulting from the primary loss in rod photoreceptors and later followed by the secondary loss in cone photoreceptors, CRDs reflect the opposite sequence of events. CRD is characterized by primary cone involvement, or, sometimes, by concomitant loss of both cones and rods that explains the predominant symptoms of CRDs: decreased visual acuity, color vision defects, photoaversion and decreased sensitivity in the central visual field, later followed by progressive loss in peripheral vision and night blindness. The clinical course of CRDs is generally more severe and rapid than that of RCDs, leading to earlier legal blindness and disability. At end stage, however, CRDs do not differ from RCDs. CRDs are most frequently non syndromic, but they may also be part of several syndromes, such as Bardet Biedl syndrome and Spinocerebellar Ataxia Type 7 (SCA7). Non syndromic CRDs are genetically heterogeneous (ten cloned genes and three loci have been identified so far). The four major causative genes involved in the pathogenesis of CRDs are ABCA4 (which causes Stargardt disease and also 30 to 60% of autosomal recessive CRDs), CRX and GUCY2D (which are responsible for many reported cases of autosomal dominant CRDs), and RPGR (which causes about 2/3 of X-linked RP and also an undetermined percentage of X-linked CRDs). It is likely that highly deleterious mutations in genes that otherwise cause RP or macular dystrophy may also lead to CRDs. The diagnosis of CRDs is based on clinical history, fundus examination and electroretinogram. Molecular diagnosis can be made for some genes, genetic counseling is always advised. Currently

  1. Evaluation of myocardial involvement in muscular dystrophy with Thallium-201 emission computed tomography

    SciTech Connect

    Yamamoto, S.; Kawai, N.; Matsushima, H.; Okada, M.; Yamauchi, K.; Yokota, M.; Hayashi, H.; Sotobata, I.; Sakuma, S.

    1985-05-01

    The clinical usefulness of quantitative analysis of thallium-201 emission computed tomography (ECT) for evaluation of left ventricular myocardial fibrosis was assessed on 45 patients with Duchenne(D), facioscapulohumeral(FSH), limbgirdle(LG) and myotonic(M) dystrophy. Trans-,long- and short-axial images were interpreted quantitatively using circumferential profile analysis, and the fibrotic tissue size (%FIB) was estimated by integration of hypoperfused areas in 6 to 8 consecutive short-axial slices. Lung/mediastinum count ratios (L/M ratio) were also assessed. Distinct ECT defects were found in 42 patients (all cases of D, FSH and LG, and 2 of 5 MTs). ECT defects were observed specifically in the posterolateral wall (71%) and apex (58%) in D, and were scattered in all LV walls in FSHG, LG and MT. ECG and VCG underestimated the extent of myocardial fibrosis in 17 patients (40%). Percent FIBs coincided with fibrotic tissue sizes proven by autopsy. Body-surface ECG should be influenced by cardiac position and rotation in the thorax, which were often observed in these disease entities. These factors were also assessed with ECT. The authors conclude; ECT to be useful for non-invasive evaluation of myocardial fibrosis in patients with various types of muscular dystrophy.

  2. [Congenital torticollis].

    PubMed

    Wicart, P

    2012-03-01

    Congenital torticollis is a very common postural deformity, characterized by a more or less severe retraction of sternocleidomastoid muscle. Any treatment, else that "good sense" counsels given to the parents, is indicated. The evolution is spontaneously favorable in the majority of cases before the age of one year old. The elimination of differential diagnosis (vertebral and/or neurological malformations, ocular, tumor) is the key-point. Screening of congenital hip dislocation is mandatory because the physiopathology is the same in both diseases. A remaining torticolis after 18 months of age may be an indication to sternocleidomastoid muscle lengthening.

  3. Repurposing of sodium channel antagonists as potential new anti-myotonic drugs.

    PubMed

    Matthews, E; Hanna, M G

    2014-11-01

    Myotonia is often a painful and disabling symptom which can interfere with daily motor function resulting in significant morbidity. Since myotonic disorders are rare it has generally proved difficult to obtain class I level evidence for anti-myotonic drug efficacy by performing randomized placebo controlled trials. Current treatment guidance is therefore largely based on anecdotal reports and physician experience. Despite the genetic channel heterogeneity of the myotonic disorders the sodium channel antagonists have become the main focus of pharmacological interest. Mexiletine is currently regarded as the first choice sodium channel blocker based on a recent placebo controlled randomized trial. However, some patients do not respond to mexiletine or have significant side effects limiting its use. There is a clinical need to develop additional antimyotonic agents. The study of Desaphy et al. is therefore important and provides in vitro evidence that a number of existing drugs with sodium channel blocking capability could potentially be repurposed as anti-myotonic drugs. Translation of these potentially important in vitro findings into clinical practice requires carefully designed randomized controlled trials. Here we discuss Desaphy's findings in the wider context of attempts to develop additional therapies for patients with clinically significant myotonia. PMID:25218042

  4. Clinical Trials in Retinal Dystrophies.

    PubMed

    Grob, Seanna R; Finn, Avni; Papakostas, Thanos D; Eliott, Dean

    2016-01-01

    Research development is burgeoning for genetic and cellular therapy for retinal dystrophies. These dystrophies are the focus of many research efforts due to the unique biology and accessibility of the eye, the transformative advances in ocular imaging technology that allows for in vivo monitoring, and the potential benefit people would gain from success in the field - the gift of renewed sight. Progress in the field has revealed the immense complexity of retinal dystrophies and the challenges faced by researchers in the development of this technology. This study reviews the current trials and advancements in genetic and cellular therapy in the treatment of retinal dystrophies and also discusses the current and potential future challenges. PMID:26957839

  5. Molecular Signatures of Membrane Protein Complexes Underlying Muscular Dystrophy*

    PubMed Central

    Turk, Rolf; Hsiao, Jordy J.; Smits, Melinda M.; Ng, Brandon H.; Pospisil, Tyler C.; Jones, Kayla S.; Campbell, Kevin P.; Wright, Michael E.

    2016-01-01

    Mutations in genes encoding components of the sarcolemmal dystrophin-glycoprotein complex (DGC) are responsible for a large number of muscular dystrophies. As such, molecular dissection of the DGC is expected to both reveal pathological mechanisms, and provides a biological framework for validating new DGC components. Establishment of the molecular composition of plasma-membrane protein complexes has been hampered by a lack of suitable biochemical approaches. Here we present an analytical workflow based upon the principles of protein correlation profiling that has enabled us to model the molecular composition of the DGC in mouse skeletal muscle. We also report our analysis of protein complexes in mice harboring mutations in DGC components. Bioinformatic analyses suggested that cell-adhesion pathways were under the transcriptional control of NFκB in DGC mutant mice, which is a finding that is supported by previous studies that showed NFκB-regulated pathways underlie the pathophysiology of DGC-related muscular dystrophies. Moreover, the bioinformatic analyses suggested that inflammatory and compensatory mechanisms were activated in skeletal muscle of DGC mutant mice. Additionally, this proteomic study provides a molecular framework to refine our understanding of the DGC, identification of protein biomarkers of neuromuscular disease, and pharmacological interrogation of the DGC in adult skeletal muscle https://www.mda.org/disease/congenital-muscular-dystrophy/research. PMID:27099343

  6. Congenital Defects.

    ERIC Educational Resources Information Center

    Goldman, Allen S.; And Others

    There are two general categories (not necessarily mutually exclusive) of congenital defects: (1) abnormalities that have an hereditary basis, such as single and multiple genes, or chromosomal abberration; and (2) abnormalities that are caused by nonhereditary factors, such as malnutrition, maternal disease, radiation, infections, drugs, or…

  7. Congenital amusias.

    PubMed

    Tillmann, B; Albouy, P; Caclin, A

    2015-01-01

    In contrast to the sophisticated music processing reported in the general population, individuals with congenital amusia show deficits in music perception and production. Congenital amusia occurs without brain damage, sensory or cognitive deficits, and has been suggested as a lifelong deficit with genetic origin. Even though recognized for a long time, this disorder has been systematically studied only relatively recently for its behavioral and neural correlates. The currently most investigated hypothesis about the underlying deficits concerns the pitch dimension, notably with impaired pitch discrimination and memory. Anatomic and functional investigations of pitch processing revealed that the amusic brain presents abnormalities in the auditory and inferior frontal cortices, associated with decreased connectivity between these structures. The deficit also impairs processing of pitch in speech material and processing of the time dimension in music for some of the amusic individuals, but does not seem to affect spatial processing. Some studies suggest at least partial dissociation in the disorder between perception and production. Recent studies revealed spared implicit pitch perception in congenital amusia, supporting the power of implicit cognition in the music domain. Current challenges consist in defining different subtypes of congenital amusia as well as developing rehabilitation programs for this "musical handicap." PMID:25726292

  8. Fuchs’ corneal dystrophy

    PubMed Central

    Eghrari, Allen O; Gottsch, John D

    2010-01-01

    Fuchs’ corneal dystrophy (FCD) is a progressive, hereditary disease of the cornea first described a century ago by the Austrian ophthalmologist Ernst Fuchs. Patients often present in the fifth to sixth decade of life with blurry morning vision that increases in duration as the disease progresses. Primarily a condition of the posterior cornea, characteristic features include the formation of focal excrescences of Descemet membrane termed ‘guttae’, loss of endothelial cell density and end-stage disease manifested by corneal edema and the formation of epithelial bullae. Recent advances in our understanding of the genetic and pathophysiological mechanisms of the disease, as well as the application of new imaging modalities and less invasive surgical procedures, present new opportunities for improved outcomes among patients with FCD. PMID:20625449

  9. Myotonic dystrophy protein kinase (DMPK) induces actin cytoskeletal reorganization and apoptotic-like blebbing in lens cells

    NASA Technical Reports Server (NTRS)

    Jin, S.; Shimizu, M.; Balasubramanyam, A.; Epstein, H. F.

    2000-01-01

    DMPK, the product of the DM locus, is a member of the same family of serine-threonine protein kinases as the Rho-associated enzymes. In DM, membrane inclusions accumulate in lens fiber cells producing cataracts. Overexpression of DMPK in cultured lens epithelial cells led to apoptotic-like blebbing of the plasma membrane and reorganization of the actin cytoskeleton. Enzymatically active DMPK was necessary for both effects; inactive mutant DMPK protein did not produce either effect. Active RhoA but not constitutive GDP-state mutant protein produced similar effects as DMPK. The similar actions of DMPK and RhoA suggest that they may function in the same regulatory network. The observed effects of DMPK may be relevant to the removal of membrane organelles during normal lens differentiation and the retention of intracellular membranes in DM lenses. Copyright 2000 Wiley-Liss, Inc.

  10. What Are the Treatments for Muscular Dystrophy?

    MedlinePlus

    ... Resources and Publications What are the treatments for muscular dystrophy? Skip sharing on social media links Share this: ... available to stop or reverse any form of muscular dystrophy (MD). Instead, certain therapies and medications aim to ...

  11. Congenital Hydrocephalus.

    PubMed

    Estey, Chelsie M

    2016-03-01

    There are several types of hydrocephalus, which are characterized based on the location of the cerebrospinal fluid (CSF) accumulation. Physical features of animals with congenital hydrocephalus may include a dome-shaped skull, persistent fontanelle, and bilateral ventrolateral strabismus. Medical therapy involves decreasing the production of CSF. The most common surgical treatment is placement of a ventriculoperitoneal shunt. Postoperative complications may include infection, blockage, drainage abnormalities, and mechanical failure.

  12. [Congenital aniridia].

    PubMed

    Chiruţa, Daria; Stan, Cristina

    2014-01-01

    Aniridia is a rare congenital, hereditary, bilateral disease which is associated with various systemic and ocular defects. We present the case of a 61 year old patient who was admitted in the hospital of ophthalmology Cluj Napoca, for the symptoms caused by the ocular defects associated with aniridia. In this case, aniridia is autosomal dominant transmitted with incomplete penetrance and it is not accompanied by any systemic defects. The disease also affects three of her sons and two nephews of the patient.

  13. Rare Muscular Dystrophies: Congenital, Distal, Emery-Dreifuss and Oculopharyngeal Muscular Dystrophies

    MedlinePlus

    ... to live with muscles that grow weaker over time, but you don’t have to let MD keep you from pursuing an education, career, family, travel — anything you want. People with disabilities have more ...

  14. Molecular characterization of co-occurring Duchenne muscular dystrophy and X-linked oculo-facio-cardio-dental syndrome in a girl.

    PubMed

    Jiang, Yong-hui; Fang, Ping; Adesina, Adekunle M; Furman, Patricia; Johnston, Jennifer J; Biesecker, Leslie G; Brown, Chester W

    2009-06-01

    Duchenne muscular dystrophy is an X-linked condition at the severe end of the spectrum of dystrophinopathies. Females with dystrophin mutations are at risk for cardiomyopathy, but are usually asymptomatic during childhood. However, some girls can exhibit features of Duchenne muscular dystrophy because of skewed X-inactivation, aneuploidy, or chromosomal rearrangement. Oculo-facio-cardio-dental syndrome is a rare X-linked disorder, lethal in males, that comprises microphthalmia, congenital cataracts, congenital heart defect, canine radiculomegaly, and digital anomalies. We report on a 7-year-old girl who was referred for muscular hypotonia, with clinical features of Duchenne muscular dystrophy, including elevated serum creatine phosphokinase, pseudohypertrophy of calf muscles, and muscle weakness, which became evident at 3 years of age. In addition, she had multiple congenital anomalies including atrial septal defect, cataracts, dental and digital anomalies, a constellation that suggested the diagnosis of oculo-facio-cardio-dental syndrome, a condition caused by mutations in BCOR. Immunohistochemistry and Western blot analysis of muscle, and mutation analysis of DMD showed a maternally inherited deletion of exons 30-43, confirming the diagnosis of Duchenne muscular dystrophy. Studies of lymphocytes showed essentially complete skewing of X-inactivation. Mutation analysis of BCOR revealed a de novo frameshift mutation (c.1005delC). Thus, we report for the first time on an individual with the co-occurrence of Duchenne muscular dystrophy and oculo-facio-cardio-dental syndrome. PMID:19449433

  15. Overexpression of LARGE suppresses muscle regeneration via down-regulation of insulin-like growth factor 1 and aggravates muscular dystrophy in mice.

    PubMed

    Saito, Fumiaki; Kanagawa, Motoi; Ikeda, Miki; Hagiwara, Hiroki; Masaki, Toshihiro; Ohkuma, Hidehiko; Katanosaka, Yuki; Shimizu, Teruo; Sonoo, Masahiro; Toda, Tatsushi; Matsumura, Kiichiro

    2014-09-01

    Several types of muscular dystrophy are caused by defective linkage between α-dystroglycan (α-DG) and laminin. Among these, dystroglycanopathy, including Fukuyama-type congenital muscular dystrophy (FCMD), results from abnormal glycosylation of α-DG. Recent studies have shown that like-acetylglucosaminyltransferase (LARGE) strongly enhances the laminin-binding activity of α-DG. Therefore, restoration of the α-DG-laminin linkage by LARGE is considered one of the most promising possible therapies for muscular dystrophy. In this study, we generated transgenic mice that overexpress LARGE (LARGE Tg) and crossed them with dy(2J) mice and fukutin conditional knockout mice, a model for laminin α2-deficient congenital muscular dystrophy (MDC1A) and FCMD, respectively. Remarkably, in both the strains, the transgenic overexpression of LARGE resulted in an aggravation of muscular dystrophy. Using morphometric analyses, we found that the deterioration of muscle pathology was caused by suppression of muscle regeneration. Overexpression of LARGE in C2C12 cells further demonstrated defects in myotube formation. Interestingly, a decreased expression of insulin-like growth factor 1 (IGF-1) was identified in both LARGE Tg mice and LARGE-overexpressing C2C12 myotubes. Supplementing the C2C12 cells with IGF-1 restored the defective myotube formation. Taken together, our findings indicate that the overexpression of LARGE aggravates muscular dystrophy by suppressing the muscle regeneration and this adverse effect is mediated via reduced expression of IGF-1.

  16. Congenital hypoaldosteronism.

    PubMed

    Sethupathi, Vanathi; Vijayakumar, M; Janakiraman, Lalitha; Nammalwar, B R

    2008-08-01

    Congenital hypoaldosteronism due to an isolated aldosterone biosynthesis defect is rare. We report a 4 month old female infant who presented with failure to thrive, persistent hyponatremia and hyperkalemia. Investigations revealed normal serum 17 hydroxy progesterone and cortisol. A decreased serum aldosterone and serum 18 hydroxy corticosterone levels with a low 18 hydroxy corticosterone: aldosterone ratio was suggestive of corticosterone methyl oxidase type I deficiency. She was started on fludrocortisone replacement therapy with a subsequent normalization of electrolytes. Further molecular analysis is needed to ascertain the precise nature of the mutation.

  17. A Nonsense Variant in COL6A1 in Landseer Dogs with Muscular Dystrophy

    PubMed Central

    Steffen, Frank; Bilzer, Thomas; Brands, Jan; Golini, Lorenzo; Jagannathan, Vidhya; Wiedmer, Michaela; Drögemüller, Michaela; Drögemüller, Cord; Leeb, Tosso

    2015-01-01

    A novel canine muscular dystrophy in Landseer dogs was observed. We had access to five affected dogs from two litters. The clinical signs started at a few weeks of age, and the severe progressive muscle weakness led to euthanasia between 5 and 15 months of age. The pedigrees of the affected dogs suggested a monogenic autosomal-recessive inheritance of the trait. Linkage and homozygosity mapping indicated two potential genome segments for the causative variant on chromosomes 10 and 31 harboring a total of 4.8 Mb of DNA or 0.2% of the canine genome. Using the Illumina sequencing technology, we obtained a whole-genome sequence from one affected Landseer. Variants were called with respect to the dog reference genome and compared with the genetic variants of 170 control dogs from other breeds. The affected Landseer dog was homozygous for a single, private nonsynonymous variant in the critical intervals, a nonsense variant in the COL6A1 gene (Chr31:39,303,964G>T; COL6A1:c.289G>T; p.E97*). Genotypes at this variant showed perfect concordance with the muscular dystrophy phenotype in all five cases and more than 1000 control dogs. Variants in the human COL6A1 gene cause Bethlem myopathy or Ullrich congenital muscular dystrophy. We therefore conclude that the identified canine COL6A1 variant is most likely causative for the observed muscular dystrophy in Landseer dogs. On the basis of the nature of the genetic variant in Landseer dogs and their severe clinical phenotype these dogs represent a model for human Ullrich congenital muscular dystrophy. PMID:26438297

  18. A Nonsense Variant in COL6A1 in Landseer Dogs with Muscular Dystrophy.

    PubMed

    Steffen, Frank; Bilzer, Thomas; Brands, Jan; Golini, Lorenzo; Jagannathan, Vidhya; Wiedmer, Michaela; Drögemüller, Michaela; Drögemüller, Cord; Leeb, Tosso

    2015-12-01

    A novel canine muscular dystrophy in Landseer dogs was observed. We had access to five affected dogs from two litters. The clinical signs started at a few weeks of age, and the severe progressive muscle weakness led to euthanasia between 5 and 15 months of age. The pedigrees of the affected dogs suggested a monogenic autosomal-recessive inheritance of the trait. Linkage and homozygosity mapping indicated two potential genome segments for the causative variant on chromosomes 10 and 31 harboring a total of 4.8 Mb of DNA or 0.2% of the canine genome. Using the Illumina sequencing technology, we obtained a whole-genome sequence from one affected Landseer. Variants were called with respect to the dog reference genome and compared with the genetic variants of 170 control dogs from other breeds. The affected Landseer dog was homozygous for a single, private nonsynonymous variant in the critical intervals, a nonsense variant in the COL6A1 gene (Chr31:39,303,964G>T; COL6A1:c.289G>T; p.E97*). Genotypes at this variant showed perfect concordance with the muscular dystrophy phenotype in all five cases and more than 1000 control dogs. Variants in the human COL6A1 gene cause Bethlem myopathy or Ullrich congenital muscular dystrophy. We therefore conclude that the identified canine COL6A1 variant is most likely causative for the observed muscular dystrophy in Landseer dogs. On the basis of the nature of the genetic variant in Landseer dogs and their severe clinical phenotype these dogs represent a model for human Ullrich congenital muscular dystrophy. PMID:26438297

  19. A Nonsense Variant in COL6A1 in Landseer Dogs with Muscular Dystrophy.

    PubMed

    Steffen, Frank; Bilzer, Thomas; Brands, Jan; Golini, Lorenzo; Jagannathan, Vidhya; Wiedmer, Michaela; Drögemüller, Michaela; Drögemüller, Cord; Leeb, Tosso

    2015-10-04

    A novel canine muscular dystrophy in Landseer dogs was observed. We had access to five affected dogs from two litters. The clinical signs started at a few weeks of age, and the severe progressive muscle weakness led to euthanasia between 5 and 15 months of age. The pedigrees of the affected dogs suggested a monogenic autosomal-recessive inheritance of the trait. Linkage and homozygosity mapping indicated two potential genome segments for the causative variant on chromosomes 10 and 31 harboring a total of 4.8 Mb of DNA or 0.2% of the canine genome. Using the Illumina sequencing technology, we obtained a whole-genome sequence from one affected Landseer. Variants were called with respect to the dog reference genome and compared with the genetic variants of 170 control dogs from other breeds. The affected Landseer dog was homozygous for a single, private nonsynonymous variant in the critical intervals, a nonsense variant in the COL6A1 gene (Chr31:39,303,964G>T; COL6A1:c.289G>T; p.E97*). Genotypes at this variant showed perfect concordance with the muscular dystrophy phenotype in all five cases and more than 1000 control dogs. Variants in the human COL6A1 gene cause Bethlem myopathy or Ullrich congenital muscular dystrophy. We therefore conclude that the identified canine COL6A1 variant is most likely causative for the observed muscular dystrophy in Landseer dogs. On the basis of the nature of the genetic variant in Landseer dogs and their severe clinical phenotype these dogs represent a model for human Ullrich congenital muscular dystrophy.

  20. Congenital Toxoplasmosis

    PubMed Central

    McAuley, James B.

    2014-01-01

    Toxoplasmosis is caused by infection with the parasite Toxoplasma gondii. It is one of the most common parasitic infections in humans and is most typically asymptomatic. However, primary infection in a pregnant woman can cause severe and disabling disease in the developing fetus. Recent developments have included increased understanding of the role of parasite genotype in determining infectivity and disease severity. Risk factors for acquisition of infection have been better defined, and the important role of foodborne transmission has been further delineated. In addition, strategies have emerged to decrease mother-to-child transmission through prompt identification of acutely infected pregnant women followed by appropriate treatment. Refined diagnostic tools, particularly the addition of immunoglobulin G avidity testing, allow for more accurate timing of maternal infection and hence better decision making during pregnancy. Congenitally infected children can be treated, beginning in utero and continuing through the first year of life, to ameliorate the severity of disease. However, despite these many advances in our understanding of congenital toxoplasmosis prevention and treatment, significant areas of study remain: we need better drugs, well defined strategies for screening of pregnant women, improved food safety, and improved diagnostic tests. PMID:25232475

  1. Porcine models of muscular dystrophy

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Duchenne muscular dystrophy is a progressive, fatal, X-linked disease caused by a failure to accumulate the cytoskeletal protein, dystrophin. This disease is modeled by a variety of animal models including several fish models, mice, rats, and dogs. While these models have contributed substantially t...

  2. Wasting mechanisms in muscular dystrophy.

    PubMed

    Shin, Jonghyun; Tajrishi, Marjan M; Ogura, Yuji; Kumar, Ashok

    2013-10-01

    Muscular dystrophy is a group of more than 30 different clinical genetic disorders that are characterized by progressive skeletal muscle wasting and degeneration. Primary deficiency of specific extracellular matrix, sarcoplasmic, cytoskeletal, or nuclear membrane protein results in several secondary changes such as sarcolemmal instability, calcium influx, fiber necrosis, oxidative stress, inflammatory response, breakdown of extracellular matrix, and eventually fibrosis which leads to loss of ambulance and cardiac and respiratory failure. A number of molecular processes have now been identified which hasten disease progression in human patients and animal models of muscular dystrophy. Accumulating evidence further suggests that aberrant activation of several signaling pathways aggravate pathological cascades in dystrophic muscle. Although replacement of defective gene with wild-type is paramount to cure, management of secondary pathological changes has enormous potential to improving the quality of life and extending lifespan of muscular dystrophy patients. In this article, we have reviewed major cellular and molecular mechanisms leading to muscle wasting in muscular dystrophy. This article is part of a Directed Issue entitled: Molecular basis of muscle wasting.

  3. Genetics Home Reference: Emery-Dreifuss muscular dystrophy

    MedlinePlus

    ... Health Conditions Emery-Dreifuss muscular dystrophy Emery-Dreifuss muscular dystrophy Enable Javascript to view the expand/collapse boxes. ... PDF Open All Close All Description Emery-Dreifuss muscular dystrophy is a condition that chiefly affects muscles used ...

  4. Genetics Home Reference: Duchenne and Becker muscular dystrophy

    MedlinePlus

    ... Duchenne and Becker muscular dystrophy Duchenne and Becker muscular dystrophy Enable Javascript to view the expand/collapse boxes. Download PDF Open All Close All Description Muscular dystrophies are a group of genetic conditions characterized by ...

  5. Pregnancy and delivery in Leyden-Möbius muscular dystrophy. Case Report.

    PubMed

    Vavrinkova, Blanka; Binder, Tomas

    2015-01-01

    Leyden-Möbius muscular dystrophy is an autosomal recessive hereditary disease of unknown aetiology; it is a congenital disorder of protein metabolism primarily affecting proximal muscle groups leading to progressive muscular dystrophy. It later spreads to the muscles of the pelvic floor and lower extremities. The estimated incidence is 1:200,000. This paper describe a case of pregnancy and delivery in woman with progressive Leyden-Moebius muscular dystrophy. Cesarean section was performed due to progression of the underlying disease. First postoperative day DIC occure and surgical revision of abdominal cavity was performed. Although the uterine suture was strong, diffuse bleeding was present. Blood was not coagulating. Supravaginal amputation of the uterus was performed including left-sided adnexectomy due to bleeding from the left ovarium. Due to the severity of the condition and assumed necessity of long-term controlled ventilation, the patient was transferred to the intensive medicine department. She was dismissed home after 91 days of hospitalisation. Gravidity in advanced muscular dystrophy is rare and associated with a high risk. Due to muscle weakness, diaphragm weakness, atrophy of individual muscle groups, spine deformities and often dislocation of thoracic organs, these patients cannot avoid the caesarean section to end their pregnancy, followed by prolonged intubation and controlled ventilation. During pregnancy, the growing uterus elevates the diaphragm and impairs breathing. Therefore, pregnancies in such patients will probably always have to be ended prematurely. PMID:26313391

  6. Congenital hypothyroidism.

    PubMed

    Rastogi, Maynika V; LaFranchi, Stephen H

    2010-01-01

    Congenital hypothyroidism (CH) occurs in approximately 1:2,000 to 1:4,000 newborns. The clinical manifestations are often subtle or not present at birth. This likely is due to trans-placental passage of some maternal thyroid hormone, while many infants have some thyroid production of their own. Common symptoms include decreased activity and increased sleep, feeding difficulty, constipation, and prolonged jaundice. On examination, common signs include myxedematous facies, large fontanels, macroglossia, a distended abdomen with umbilical hernia, and hypotonia. CH is classified into permanent and transient forms, which in turn can be divided into primary, secondary, or peripheral etiologies. Thyroid dysgenesis accounts for 85% of permanent, primary CH, while inborn errors of thyroid hormone biosynthesis (dyshormonogeneses) account for 10-15% of cases. Secondary or central CH may occur with isolated TSH deficiency, but more commonly it is associated with congenital hypopitiutarism. Transient CH most commonly occurs in preterm infants born in areas of endemic iodine deficiency. In countries with newborn screening programs in place, infants with CH are diagnosed after detection by screening tests. The diagnosis should be confirmed by finding an elevated serum TSH and low T4 or free T4 level. Other diagnostic tests, such as thyroid radionuclide uptake and scan, thyroid sonography, or serum thyroglobulin determination may help pinpoint the underlying etiology, although treatment may be started without these tests. Levothyroxine is the treatment of choice; the recommended starting dose is 10 to 15 mcg/kg/day. The immediate goals of treatment are to rapidly raise the serum T4 above 130 nmol/L (10 ug/dL) and normalize serum TSH levels. Frequent laboratory monitoring in infancy is essential to ensure optimal neurocognitive outcome. Serum TSH and free T4 should be measured every 1-2 months in the first 6 months of life and every 3-4 months thereafter. In general, the prognosis

  7. A gene for autosomal dominant progressive cone dystrophy (CORD5) maps to chromosome 17p12-p13

    SciTech Connect

    Balciuniene, J.; Holmgren, G.; Forsman, K.

    1995-11-20

    Inherited retinal dystrophy is a common cause of visual impairment. Cone dystrophy affects the cone function and is manifested as progressive loss of the central vision, defective color vision, and photophobia. Linkage was demonstrated between progressive cone dystrophy (CORD5) and genetic markers on chromosome 17p12-p13 in a five-generation family. Multipoint analysis gave a maximum lod score of 7.72 at the marker D17S938. Recombinant haplotypes in the family suggest that the cone dystrophy locus is located in a 25-cM interval between the markers D17S926/D17S849 and D17S804/D17S945. Furthermore, one recombination was detected between the disease locus and a microsatellite marker in the candidate gene RCV1, encoding the retinal protein recoverin. Two additional candidate genes encoding retinal guanylate cyclase (GUC2D) and pigment epithelium-derived factor (PEDF) are located at 17p13.1. Moreover, loci for retinitis pigmentosa and Leber congenital amaurosis have been mapped to the same region. Identification of the cone dystrophy locus may be of importance not only for identifying functional genes in the cone system, but also for identifying genes for other retinal disorders. 34 refs., 3 figs., 2 tabs.

  8. Congenital hypothyroidism.

    PubMed

    Abduljabbar, Mohammad A; Afifi, Ashraf M

    2012-01-01

    Congenital hypothyroidism (CH) is defined as thyroid hormone deficiency present at birth. Babies with CH who are not identified and treated promptly develop severe mental retardation. Most of the babies with CH do not manifest the typical known signs and symptoms of hypothyroidism, and this is most likely due to transplacental passage of some maternal thyroid hormone in addition to some residual neonatal thyroid function, as might be seen with thyroid hypoplasia, an ectopic gland, or mild dyshormonogenesis. Screening for CH has enabled the virtual eradication of the devastating effects of mental retardation due to sporadic CH in most developed countries of the world. CH is classified into permanent and transient forms, which in turn can be divided into primary, secondary, or peripheral etiologies. Permanent CH refers to a persistent deficiency of thyroid hormone that requires life-long treatment. Transient CH refers to a temporary deficiency of thyroid hormone that is discovered at birth but recovers to normal in the first few months or years of life. In the last several decades, there have been exciting advances in our understanding of fetal and neonatal thyroid physiology. In addition, advances in molecular biology have helped in understanding the early events in thyroid gland embryogenesis, mechanisms of thyroid action in the brain, the molecular basis for many of the inborn errors of thyroid hormonogenesis, and thyroid hormone action. However, many questions and challenges are still not answered. For example, the increasing numbers of surviving small and premature neonates with abnormalities in thyroid function need definite diagnostic criteria and whether they require medical therapy. Another challenge is the dilemma of finding the best screening methodology that is sensitive and cost effective. PMID:22570946

  9. Congenital myopathies

    PubMed Central

    Colombo, Irene; Scoto, Mariacristina; Manzur, Adnan Y.; Robb, Stephanie A.; Maggi, Lorenzo; Gowda, Vasantha; Cullup, Thomas; Yau, Michael; Phadke, Rahul; Sewry, Caroline; Jungbluth, Heinz

    2015-01-01

    Objective: To assess the natural history of congenital myopathies (CMs) due to different genotypes. Methods: Retrospective cross-sectional study based on case-note review of 125 patients affected by CM, followed at a single pediatric neuromuscular center, between 1984 and 2012. Results: Genetic characterization was achieved in 99 of 125 cases (79.2%), with RYR1 most frequently implicated (44/125). Neonatal/infantile onset was observed in 76%. At birth, 30.4% required respiratory support, and 25.2% nasogastric feeding. Twelve percent died, mainly within the first year, associated with mutations in ACTA1, MTM1, or KLHL40. All RYR1-mutated cases survived and did not require long-term ventilator support including those with severe neonatal onset; however, recessive cases were more likely to require gastrostomy insertion (p = 0.0028) compared with dominant cases. Independent ambulation was achieved in 74.1% of all patients; 62.9% were late walkers. Among ambulant patients, 9% eventually became wheelchair-dependent. Scoliosis of variable severity was reported in 40%, with 1/3 of (both ambulant and nonambulant) patients requiring surgery. Bulbar involvement was present in 46.4% and required gastrostomy placement in 28.8% (at a mean age of 2.7 years). Respiratory impairment of variable severity was a feature in 64.1%; approximately half of these patients required nocturnal noninvasive ventilation due to respiratory failure (at a mean age of 8.5 years). Conclusions: We describe the long-term outcome of a large cohort of patients with CMs. While overall course is stable, we demonstrate a wide clinical spectrum with motor deterioration in a subset of cases. Severity in the neonatal/infantile period is critical for survival, with clear genotype-phenotype correlations that may inform future counseling. PMID:25428687

  10. Cardiac transplantation in Becker muscular dystrophy.

    PubMed

    Quinlivan, R M; Dubowitz, V

    1992-01-01

    Becker muscular dystrophy is associated with abnormal cardiac features in about 75% of cases; up to one-third will develop ventricular dilatation leading to congestive cardiac failure. As this form of muscular dystrophy is relatively benign, failure to respond to medical treatment warrants assessment for cardiac transplantation.

  11. Corneal dystrophy in the dog and cat.

    PubMed

    Cooley, P L; Dice, P F

    1990-05-01

    Two types of epithelial dystrophy have been described in dogs, one each in the Boxer and Shetland Sheepdog breeds, both of which can be associated with corneal erosions. Medical therapy is recommended when erosions or tear film abnormalities are present. Stromal dystrophies documented in dogs appear to be a primary lipid deposition in various layers of the stroma, depending on the breed. Stromal dystrophies seldom lead to loss of vision, but vision loss has been observed in middle aged Airedale Terriers and aged Siberian Huskies. Treatment is usually unnecessary. The dog demonstrates two types of endothelial dystrophy, one of which (posterior polymorphous dystrophy in the American Cocker Spaniel) does not lead to corneal edema. Endothelial dystrophy observed in the Boston Terrier, Chihuahua, and other breeds is associated with progressive corneal edema, which can lead to bullous keratopathy and corneal erosions. Stromal and endothelial dystrophies, both of which are associated with rapid progression of corneal edema, occur rarely in the cat. Treatment of dystrophies with progressive corneal edema is symptomatic and palliative.

  12. Congenital Intralabyrinthine Cholesteatoma

    PubMed Central

    Prasad, Sanjay; Prasad, Kiran; Azadarmaki, Roya

    2014-01-01

    A patient with a congenital intralabyrinthine cholesteatoma is presented. High-resolution computerized tomographic scans and intraoperative photomicrographs display features of intralabyrinthine extension. We discuss pathogenetic theories for the development of congenital intralabyrinthine cholesteatoma. The distinction of this condition from congenital cholesteatoma with labyrinthine erosion is discussed. PMID:25057421

  13. Duchenne muscular dystrophy: current cell therapies

    PubMed Central

    Sienkiewicz, Dorota; Okurowska-Zawada, Bożena; Paszko-Patej, Grażyna; Kawnik, Katarzyna

    2015-01-01

    Duchenne muscular dystrophy is a genetically determined X-linked disease and the most common, progressive pediatric muscle disorder. For decades, research has been conducted to find an effective therapy. This review presents current therapeutic methods for Duchenne muscular dystrophy, based on scientific articles in English published mainly in the period 2000 to 2014. We used the PubMed database to identify and review the most important studies. An analysis of contemporary studies of stem cell therapy and the use of granulocyte colony-stimulating factor (G-CSF) in muscular dystrophy was performed. PMID:26136844

  14. Comparative study of thallium-201 single-photon emission computed tomography and electrocardiography in Duchenne and other types of muscular dystrophy

    SciTech Connect

    Yamamoto, S.; Matsushima, H.; Suzuki, A.; Sotobata, I.; Indo, T.; Matsuoka, Y.

    1988-04-01

    Single-photon emission computed tomography (SPECT) using thallium-201 was compared with 12-lead electrocardiography (ECG) in patients with Duchenne (29), facioscapulohumeral (7), limb-girdle (6) and myotonic (5) dystrophies, by dividing the left ventricular (LV) wall into 5 segments. SPECT showed thallium defects (37 patients, mostly in the posteroapical wall), malrotation (23), apical aneurysm (5) and dilatation (7). ECG showed abnormal QRS (36 patients), particularly as a posterolateral pattern (13). Both methods of assessment were normal in only 7 patients. The Duchenne type frequently showed both a thallium defect (particularly in the posteroapical wall) and an abnormal QRS (predominantly in the posterolateral wall); the 3 other types showed abnormalities over the 5 LV wall segments in both tests. The percent of agreement between the 2 tests was 64, 66, 70, 72 and 72 for the lateral, apical, anteroseptal, posterior and inferior walls, respectively. The 2 tests were discordant in 31% of the LV wall, with SPECT (+) but ECG (-) in 21% (mostly in the apicoinferior wall) and SPECT (-) but ECG (+) in 10% (mostly in the lateral wall). Some patients showed large SPECT hypoperfusion despite minimal electrocardiographic changes. ECG thus appeared to underestimate LV fibrosis and to reflect posteroapical rather than posterolateral dystrophy in its posterolateral QRS pattern. In this disease, extensive SPECT hypoperfusion was also shown, irrespective of clinical subtype and skeletal involvement.

  15. [Muscular Dystrophies Involving the Retinal Function].

    PubMed

    Jägle, H

    2016-03-01

    Muscular dystrophies are rare disorders, with an incidence of approx. 20 in 100 000. Some dystrophies also affect retinal or optic nerve function. In such cases, the ophthalmological findings may be critical for differential diagnosis or patient counseling. For example in Duchenne muscular dystrophy, where the alteration in retinal function seems to reflect cerebral involvement. Other important forms are mitochondrial and metabolic disorders, such as the Kearns-Sayre syndrome and the Refsum syndrome. Molecular genetic analysis has become a major tool for differential diagnosis, but may be complex and demanding. This article gives an overview of major muscular dystrophies involving retinal function and their genetic origin, in order to guide differential diagnosis.

  16. Physical Therapy and Facioscapulohumeral Muscular Dystrophy (FSHD)

    MedlinePlus

    Physical Therapy & FSHD Facioscapulohumeral Muscular Dystrophy A Guide for Patients & Physical Therapists Authors: Wendy M. King, P.T., ... expertise and patient preferences. The goals of any physical therapy plan of care are to assist patients to:  ...

  17. The Muscular Dystrophies: From Genes to Therapies

    PubMed Central

    Porter, Neil C; Bloch, Robert J

    2015-01-01

    The genetic basis of many muscular disorders, including many of the more common muscular dystrophies, is now known. Clinically, the recent genetic advances have improved diagnostic capabilities, but they have not yet provided clues about treatment or management. Thanks to better management strategies and therapeutic interventions, however, many patients with a muscular dystrophy are more active and are living longer. Physical therapists, therefore, are more likely to see a patient with a muscular dystrophy, so understanding these muscle disorders and their management is essential. Physical therapy offers the most promise in caring for the majority of patients with these conditions, because it is unlikely that advances in gene therapy will significantly alter their clinical treatment in the near future. This perspective covers some of the basic molecular biological advances together with the clinical manifestations of the muscular dystrophies and the latest approaches to their management. PMID:16305275

  18. Genetics Home Reference: Bietti crystalline dystrophy

    MedlinePlus

    ... on PubMed Central Mansour AM, Uwaydat SH, Chan CC. Long-term follow-up in Bietti crystalline dystrophy. ... VD, Zhang J, Gesualdo C, Corte MD, Chan CC, Fielding Hejtmancik J, Simonelli F. An atypical form ...

  19. Targeting latent TGFβ release in muscular dystrophy.

    PubMed

    Ceco, Ermelinda; Bogdanovich, Sasha; Gardner, Brandon; Miller, Tamari; DeJesus, Adam; Earley, Judy U; Hadhazy, Michele; Smith, Lucas R; Barton, Elisabeth R; Molkentin, Jeffery D; McNally, Elizabeth M

    2014-10-22

    Latent transforming growth factor-β (TGFβ) binding proteins (LTBPs) bind to inactive TGFβ in the extracellular matrix. In mice, muscular dystrophy symptoms are intensified by a genetic polymorphism that changes the hinge region of LTBP, leading to increased proteolytic susceptibility and TGFβ release. We have found that the hinge region of human LTBP4 was also readily proteolysed and that proteolysis could be blocked by an antibody to the hinge region. Transgenic mice were generated to carry a bacterial artificial chromosome encoding the human LTBP4 gene. These transgenic mice displayed larger myofibers, increased damage after muscle injury, and enhanced TGFβ signaling. In the mdx mouse model of Duchenne muscular dystrophy, the human LTBP4 transgene exacerbated muscular dystrophy symptoms and resulted in weaker muscles with an increased inflammatory infiltrate and greater LTBP4 cleavage in vivo. Blocking LTBP4 cleavage may be a therapeutic strategy to reduce TGFβ release and activity and decrease inflammation and muscle damage in muscular dystrophy.

  20. Genetics Home Reference: vitelliform macular dystrophy

    MedlinePlus

    ... faces. Vitelliform macular dystrophy causes a fatty yellow pigment (lipofuscin) to build up in cells underlying the ... structures in these cells that contain light-sensing pigments. It is unclear why PRPH2 mutations affect only ...

  1. Reflex sympathetic dystrophy following traumatic myelopathy.

    PubMed

    Wainapel, S F

    1984-04-01

    Two cases of reflex sympathetic dystrophy in the upper extremity of patients with traumatic cervical spinal cord injuries are reported. Both patients had very incomplete lesions with early neurological recovery, suggesting an underlying central cord syndrome. Although reflex sympathetic dystrophy is often seen following stroke, it has only rarely been documented in traumatic myelopathy, and it should be considered in the differential diagnosis of unexplained pain syndromes in the extremities of paraplegic or quadriplegic patients. PMID:6728500

  2. Duchenne muscular dystrophy: the management of scoliosis

    PubMed Central

    Gardner, Adrian C.; Roper, Helen P.; Chikermane, Ashish A.; Tatman, Andrew J.

    2016-01-01

    This study summaries the current management of scoliosis in patients with Duchenne Muscular Dystrophy. A literature review of Medline was performed and the collected articles critically appraised. This literature is discussed to give an overview of the current management of scoliosis within Duchenne Muscular Dystrophy. Importantly, improvements in respiratory care, the use of steroids and improving surgical techniques have allowed patients to maintain quality of life and improved life expectancy in this patient group. PMID:27757431

  3. Congenital myopathies: an update.

    PubMed

    Nance, Jessica R; Dowling, James J; Gibbs, Elizabeth M; Bönnemann, Carsten G

    2012-04-01

    Congenital myopathy is a clinicopathological concept of characteristic histopathological findings on muscle biopsy in a patient with early-onset weakness. Three main categories are recognized within the classical congenital myopathies: nemaline myopathy, core myopathy, and centronuclear myopathy. Recent evidence of overlapping clinical and histological features between the classical forms and their different genetic entities suggests that there may be shared pathomechanisms between the congenital myopathies. Animal models, especially mouse and zebrafish, have been especially helpful in elucidating such pathomechanisms associated with the congenital myopathies and provide models in which future therapies can be investigated. PMID:22392505

  4. Genetics Home Reference: congenital hypothyroidism

    MedlinePlus

    ... Understand Genetics Home Health Conditions congenital hypothyroidism congenital hypothyroidism Enable Javascript to view the expand/collapse boxes. Download PDF Open All Close All Description Congenital hypothyroidism is a partial or complete loss of function ...

  5. Feasibility of monitoring muscle health in microgravity environments using Myoton technology.

    PubMed

    Schneider, Stefan; Peipsi, Aleko; Stokes, Maria; Knicker, Axel; Abeln, Vera

    2015-01-01

    Physical exercise is important for people living under extreme environmental conditions to stay healthy. Particularly in space, exercise can partially counteract the loss of muscle mass and muscle strength caused by microgravity. Monitoring the adaptation of the musculoskeletal system to assess muscle quality and devise individual training programmes is highly desirable but is restricted by practical, technical and time constraints on board the International Space Station. This study aimed to test the feasibility of using myometric measurements to monitor the mechanical properties of skeletal muscles and tendons in weightlessness during parabolic flights. The mechanical properties (frequency, decrement, stiffness relaxation time and creep) of the m. gastrocnemius, m. erector spinae and Achilles tendon were assessed using the hand-held MyotonPRO device in 11 healthy participants (aged 47 ± 9 years) in normal gravity as well as in microgravity during two parabolic flight campaigns. Results showed significant (p < .05-.001) changes in all mechanical properties of both muscles and the Achilles tendon, indicating a more relaxed tissue state in microgravity. Recordings from a phantom rubber material with the device in a test rig confirmed that the device itself was not affected by gravity, as changes between gravity conditions that were too small (<1 %) to explain the changes observed in the tissues. It is concluded that myometric measurements are a feasible, easy-to-use and non-invasive approach to monitor muscle health in extreme conditions that prohibit many other methods. Real-time assessment of the quality of a muscle being exposed to the negative effect of microgravity and also the positive effects of muscular training could be achieved using Myoton technology.

  6. Ultrasound diagnosis of bilateral cataracts in a fetus with possible cerebro-ocular congential muscular dystrophy during the routine second trimester anomaly scan.

    PubMed

    Drought, Alexandra; Wimalasundera, Ruwan; Holder, Susan

    2015-08-01

    The finding of bilateral congenital cataracts in the fetus is rare. We report bilateral congenital cataracts detected during the routine second trimester anomaly scan, which subsequently were found to be associated with other congenital anomalies and the parents opted for a termination of pregnancy. At post-mortem, Muscle-Eye Brain disease or Walker-Warburg Syndrome was considered likely, which are autosomal recessive congenital muscular dystrophy disorders associated with cerebral, cerebellar, muscle and eye anomalies. On ultrasound, bilateral cataracts appear as echogenic, solid areas within the fetal orbits. The examination of the fetal face and orbits plays an important role in confirming fetal well-being antenatally. We propose that it should become a routine part of the structural survey of fetal anatomy during the obstetric anomaly scan. This is especially important in pregnancies previously affected by fetal cataracts or pregnancies at risk of rare genetic syndromes. PMID:27433255

  7. Ultrasound diagnosis of bilateral cataracts in a fetus with possible cerebro-ocular congential muscular dystrophy during the routine second trimester anomaly scan.

    PubMed

    Drought, Alexandra; Wimalasundera, Ruwan; Holder, Susan

    2015-08-01

    The finding of bilateral congenital cataracts in the fetus is rare. We report bilateral congenital cataracts detected during the routine second trimester anomaly scan, which subsequently were found to be associated with other congenital anomalies and the parents opted for a termination of pregnancy. At post-mortem, Muscle-Eye Brain disease or Walker-Warburg Syndrome was considered likely, which are autosomal recessive congenital muscular dystrophy disorders associated with cerebral, cerebellar, muscle and eye anomalies. On ultrasound, bilateral cataracts appear as echogenic, solid areas within the fetal orbits. The examination of the fetal face and orbits plays an important role in confirming fetal well-being antenatally. We propose that it should become a routine part of the structural survey of fetal anatomy during the obstetric anomaly scan. This is especially important in pregnancies previously affected by fetal cataracts or pregnancies at risk of rare genetic syndromes.

  8. Porcine models of muscular dystrophy.

    PubMed

    Selsby, Joshua T; Ross, Jason W; Nonneman, Dan; Hollinger, Katrin

    2015-01-01

    Duchenne muscular dystrophy is a progressive, fatal, X-linked disease caused by a failure to accumulate the cytoskeletal protein dystrophin. This disease has been studied using a variety of animal models including fish, mice, rats, and dogs. While these models have contributed substantially to our mechanistic understanding of the disease and disease progression, limitations inherent to each model have slowed the clinical advancement of therapies, which necessitates the development of novel large-animal models. Several porcine dystrophin-deficient models have been identified, although disease severity may be so severe as to limit their potential contributions to the field. We have recently identified and completed the initial characterization of a natural porcine model of dystrophin insufficiency. Muscles from these animals display characteristic focal necrosis concomitant with decreased abundance and localization of dystrophin-glycoprotein complex components. These pigs recapitulate many of the cardinal features of muscular dystrophy, have elevated serum creatine kinase activity, and preliminarily appear to display altered locomotion. They also suffer from sudden death preceded by EKG abnormalities. Pig dystrophinopathy models could allow refinement of dosing strategies in human-sized animals in preparation for clinical trials. From an animal handling perspective, these pigs can generally be treated normally, with the understanding that acute stress can lead to sudden death. In summary, the ability to create genetically modified pig models and the serendipitous discovery of genetic disease in the swine industry has resulted in the emergence of new animal tools to facilitate the critical objective of improving the quality and length of life for boys afflicted with such a devastating disease.

  9. Congenital CMV Infection

    MedlinePlus

    ... CMV Babies Born with CMV (Congenital CMV Infection) Language: English Español (Spanish) Recommend on Facebook Tweet Share Compartir ... Detection and Intervention Helping Children With Congenital CMV Language: English Español (Spanish) File Formats Help: How do I ...

  10. Congenital heat disease

    SciTech Connect

    Higgins, C.B.; Silverman, N.H.; Kersting-Somerhoff, B.A.

    1990-01-01

    The book covers the tomographic anatomy of the normal and congenitally malformed heart and tomographic imaging of the normal heat. It then compares echocardiographic evaluation and the use of MR imaging in the diagnosis and evaluation of individual congenital cardiac malformations.

  11. FDA OKs 1st Drug to Treat Duchenne Muscular Dystrophy

    MedlinePlus

    ... html FDA OKs 1st Drug to Treat Duchenne Muscular Dystrophy Exondys 51 seems to fill unmet need for ... the first drug for a rare form of muscular dystrophy. Exondys 51 (eteplirsen) was granted accelerated approval to ...

  12. Abnormalities of dystrophin, the sarcoglycans, and laminin alpha2 in the muscular dystrophies.

    PubMed Central

    Jones, K J; Kim, S S; North, K N

    1998-01-01

    Abnormalities of dystrophin, the sarcoglycans, and laminin alpha2 are responsible for a subset of the muscular dystrophies. In this study we aim to characterise the nature and frequency of abnormalities of these proteins in an Australian population and to formulate an investigative algorithm to aid in approaching the diagnosis of the muscular dystrophies. To reduce ascertainment bias, biopsies with dystrophic (n=131) and non-dystrophic myopathic (n=71) changes were studied with antibodies to dystrophin, alpha, beta, and gamma sarcoglycan, beta dystroglycan, and laminin alpha2, and results were correlated with clinical phenotype. Abnormalities of dystrophin, the sarcoglycans, or laminin alpha2 were present in 61/131 (47%) dystrophic biopsies and in 0/71 myopathic biopsies, suggesting that immunocytochemical study of dystrophin, the sarcoglycans, and laminin alpha2 may, in general, be restricted to patients with dystrophic biopsies. Two patients with mutations identified in gamma sarcoglycan had abnormal dystrophin (by immunocytochemistry and immunoblot), showing that abnormalities of dystrophin may be a secondary phenomenon. Therefore, biopsies should not be excluded from sarcoglycan analysis on the basis of abnormal dystrophin alone. The diagnostic yield was highest in those with severe, rapidly progressive limb-girdle weakness (92%). Laminin alpha2 deficiency was identified in 5/131 (4%) patients; 215 patients presented after infancy, indicating that abnormalities of laminin alpha2 are not limited to the congenital muscular dystrophy phenotype. Overall patterns of immunocytochemistry and immunoblotting provided a guide to mutation analysis and, on the basis of this study, we have formulated a diagnostic algorithm to guide the investigation of patients with muscular dystrophy. Images PMID:9610800

  13. Mutations in GMPPB cause congenital myasthenic syndrome and bridge myasthenic disorders with dystroglycanopathies.

    PubMed

    Belaya, Katsiaryna; Rodríguez Cruz, Pedro M; Liu, Wei Wei; Maxwell, Susan; McGowan, Simon; Farrugia, Maria E; Petty, Richard; Walls, Timothy J; Sedghi, Maryam; Basiri, Keivan; Yue, Wyatt W; Sarkozy, Anna; Bertoli, Marta; Pitt, Matthew; Kennett, Robin; Schaefer, Andrew; Bushby, Kate; Parton, Matt; Lochmüller, Hanns; Palace, Jacqueline; Muntoni, Francesco; Beeson, David

    2015-09-01

    Congenital myasthenic syndromes are inherited disorders that arise from impaired signal transmission at the neuromuscular junction. Mutations in at least 20 genes are known to lead to the onset of these conditions. Four of these, ALG2, ALG14, DPAGT1 and GFPT1, are involved in glycosylation. Here we identify a fifth glycosylation gene, GMPPB, where mutations cause congenital myasthenic syndrome. First, we identified recessive mutations in seven cases from five kinships defined as congenital myasthenic syndrome using decrement of compound muscle action potentials on repetitive nerve stimulation on electromyography. The mutations were present through the length of the GMPPB, and segregation, in silico analysis, exon trapping, cell transfection followed by western blots and immunostaining were used to determine pathogenicity. GMPPB congenital myasthenic syndrome cases show clinical features characteristic of congenital myasthenic syndrome subtypes that are due to defective glycosylation, with variable weakness of proximal limb muscle groups while facial and eye muscles are largely spared. However, patients with GMPPB congenital myasthenic syndrome had more prominent myopathic features that were detectable on muscle biopsies, electromyography, muscle magnetic resonance imaging, and through elevated serum creatine kinase levels. Mutations in GMPPB have recently been reported to lead to the onset of muscular dystrophy dystroglycanopathy. Analysis of four additional GMPPB-associated muscular dystrophy dystroglycanopathy cases by electromyography found that a defective neuromuscular junction component is not always present. Thus, we find mutations in GMPPB can lead to a wide spectrum of clinical features where deficit in neuromuscular transmission is the major component in a subset of cases. Clinical recognition of GMPPB-associated congenital myasthenic syndrome may be complicated by the presence of myopathic features, but correct diagnosis is important because affected

  14. Mutations in GMPPB cause congenital myasthenic syndrome and bridge myasthenic disorders with dystroglycanopathies

    PubMed Central

    Belaya, Katsiaryna; Rodríguez Cruz, Pedro M.; Liu, Wei Wei; Maxwell, Susan; McGowan, Simon; Farrugia, Maria E.; Petty, Richard; Walls, Timothy J.; Sedghi, Maryam; Basiri, Keivan; Yue, Wyatt W.; Sarkozy, Anna; Bertoli, Marta; Pitt, Matthew; Kennett, Robin; Schaefer, Andrew; Bushby, Kate; Parton, Matt; Lochmüller, Hanns; Palace, Jacqueline; Muntoni, Francesco

    2015-01-01

    Congenital myasthenic syndromes are inherited disorders that arise from impaired signal transmission at the neuromuscular junction. Mutations in at least 20 genes are known to lead to the onset of these conditions. Four of these, ALG2, ALG14, DPAGT1 and GFPT1, are involved in glycosylation. Here we identify a fifth glycosylation gene, GMPPB, where mutations cause congenital myasthenic syndrome. First, we identified recessive mutations in seven cases from five kinships defined as congenital myasthenic syndrome using decrement of compound muscle action potentials on repetitive nerve stimulation on electromyography. The mutations were present through the length of the GMPPB, and segregation, in silico analysis, exon trapping, cell transfection followed by western blots and immunostaining were used to determine pathogenicity. GMPPB congenital myasthenic syndrome cases show clinical features characteristic of congenital myasthenic syndrome subtypes that are due to defective glycosylation, with variable weakness of proximal limb muscle groups while facial and eye muscles are largely spared. However, patients with GMPPB congenital myasthenic syndrome had more prominent myopathic features that were detectable on muscle biopsies, electromyography, muscle magnetic resonance imaging, and through elevated serum creatine kinase levels. Mutations in GMPPB have recently been reported to lead to the onset of muscular dystrophy dystroglycanopathy. Analysis of four additional GMPPB-associated muscular dystrophy dystroglycanopathy cases by electromyography found that a defective neuromuscular junction component is not always present. Thus, we find mutations in GMPPB can lead to a wide spectrum of clinical features where deficit in neuromuscular transmission is the major component in a subset of cases. Clinical recognition of GMPPB-associated congenital myasthenic syndrome may be complicated by the presence of myopathic features, but correct diagnosis is important because affected

  15. Differential diagnosis of Schnyder corneal dystrophy.

    PubMed

    Weiss, Jayne S; Khemichian, Arbi J

    2011-01-01

    Schnyder corneal dystrophy (SCD) is a rare corneal dystrophy characterized by abnormally increased deposition of cholesterol and phospholipids in the cornea leading to progressive vision loss. SCD is inherited as an autosomal dominant trait with high penetrance and has been mapped to the UBIAD1 gene on chromosome 1p36.3. Although 2/3 of SCD patients also have systemic hypercholesterolemia, the incidence of hypercholesterolemia is also increased in unaffected members of SCD pedigrees. Consequently, SCD is thought to result from a local metabolic defect in the cornea. The corneal findings in SCD are very predictable depending on the age of the individual, with initial central corneal haze and/or crystals, subsequent appearance of arcus lipoides in the third decade and formation of midperipheral haze in the late fourth decade. Because only 50% of affected patients have corneal crystals, the International Committee for Classification of Corneal Dystrophies recently changed the original name of this dystrophy from Schnyder crystalline corneal dystrophy to Schnyder corneal dystrophy. Diagnosis of affected individuals without crystalline deposits is often delayed and these individuals are frequently misdiagnosed. The differential diagnosis of the SCD patient includes other diseases with crystalline deposits such as cystinosis, tyrosinemia, Bietti crystalline dystrophy, hyperuricemia/gout, multiple myeloma, monoclonal gammopathy, infectious crystalline keratopathy, and Dieffenbachia keratitis. Depositions from drugs such as gold in chrysiasis, chlorpromazine, chloroquine, and clofazamine can also result in corneal deposits and are different from SCD. Diseases of systemic lipid metabolism that cause corneal opacification, such as lecithin-cholesterol acyltransferase deficiency, fish eye disease and Tangier disease, should also be considered although these are autosomal recessive disorders. PMID:21540632

  16. Giant congenital melanocytic nevus.

    PubMed

    Viana, Ana Carolina Leite; Gontijo, Bernardo; Bittencourt, Flávia Vasques

    2013-01-01

    Giant congenital melanocytic nevus is usually defined as a melanocytic lesion present at birth that will reach a diameter ≥ 20 cm in adulthood. Its incidence is estimated in <1:20,000 newborns. Despite its rarity, this lesion is important because it may associate with severe complications such as malignant melanoma, affect the central nervous system (neurocutaneous melanosis), and have major psychosocial impact on the patient and his family due to its unsightly appearance. Giant congenital melanocytic nevus generally presents as a brown lesion, with flat or mammilated surface, well-demarcated borders and hypertrichosis. Congenital melanocytic nevus is primarily a clinical diagnosis. However, congenital nevi are histologically distinguished from acquired nevi mainly by their larger size, the spread of the nevus cells to the deep layers of the skin and by their more varied architecture and morphology. Although giant congenital melanocytic nevus is recognized as a risk factor for the development of melanoma, the precise magnitude of this risk is still controversial. The estimated lifetime risk of developing melanoma varies from 5 to 10%. On account of these uncertainties and the size of the lesions, the management of giant congenital melanocytic nevus needs individualization. Treatment may include surgical and non-surgical procedures, psychological intervention and/or clinical follow-up, with special attention to changes in color, texture or on the surface of the lesion. The only absolute indication for surgery in giant congenital melanocytic nevus is the development of a malignant neoplasm on the lesion.

  17. Genetics of congenital hypothyroidism

    PubMed Central

    Park, S; Chatterjee, V

    2005-01-01

    Congenital hypothyroidism is the most common neonatal metabolic disorder and results in severe neurodevelopmental impairment and infertility if untreated. Congenital hypothyroidism is usually sporadic but up to 2% of thyroid dysgenesis is familial, and congenital hypothyroidism caused by organification defects is often recessively inherited. The candidate genes associated with this genetically heterogeneous disorder form two main groups: those causing thyroid gland dysgenesis and those causing dyshormonogenesis. Genes associated with thyroid gland dysgenesis include the TSH receptor in non-syndromic congenital hypothyroidism, and Gsα and the thyroid transcription factors (TTF-1, TTF-2, and Pax-8), associated with different complex syndromes that include congenital hypothyroidism. Among those causing dyshormonogenesis, the thyroid peroxidase and thyroglobulin genes were initially described, and more recently PDS (Pendred syndrome), NIS (sodium iodide symporter), and THOX2 (thyroid oxidase 2) gene defects. There is also early evidence for a third group of congenital hypothyroid conditions associated with iodothyronine transporter defects associated with severe neurological sequelae. This review focuses on the genetic aspects of primary congenital hypothyroidism. PMID:15863666

  18. Muscle phenotypic variability in limb girdle muscular dystrophy 2 G.

    PubMed

    Paim, Julia F; Cotta, Ana; Vargas, Antonio P; Navarro, Monica M; Valicek, Jaquelin; Carvalho, Elmano; da-Cunha, Antonio L; Plentz, Estevão; Braz, Shelida V; Takata, Reinaldo I; Almeida, Camila F; Vainzof, Mariz

    2013-06-01

    Limb girdle muscular dystrophy type 2 G (LGMD2G) is caused by mutations in the telethonin gene. Only few families were described presenting this disease, and they are mainly Brazilians. Here, we identified one additional case carrying the same common c.157C > T mutation in the telethonin gene but with an atypical histopathological muscle pattern. In a female patient with a long duration of symptoms (46 years), muscle biopsy showed, in addition to telethonin deficiency, the presence of nemaline rods, type 1 fiber predominance, nuclear internalization, lobulated fibers, and mitochondrial paracrystalline inclusions. Her first clinical signs were identified at 8 years old, which include tiptoe walking, left lower limb deformity, and frequent falls. Ambulation loss occurred at 41 years old, and now, at 54 years old, she presented pelvic girdle atrophy, winging scapula, foot deformity with incapacity to perform ankle dorsiflexion, and absent tendon reflexes. The presence of nemaline bodies could be a secondary phenomenon, possibly associated with focal Z-line abnormalities of a long-standing disease. However, these new histopathological findings, characteristic of congenital myopathies, expand muscle phenotypic variability of telethoninopathy. PMID:23479141

  19. Genetics of Bietti Crystalline Dystrophy.

    PubMed

    Ng, Danny S C; Lai, Timothy Y Y; Ng, Tsz Kin; Pang, Chi Pui

    2016-01-01

    Bietti crystalline dystrophy (BCD) is an inherited retinal degenerative disease characterized by crystalline deposits in the retina, followed by progressive atrophy of the retinal pigment epithelium (RPE), choriocapillaris, and photoreceptors. CYP4V2 has been identified as the causative gene for BCD. The CYP4V2 gene belongs to the cytochrome P450 superfamily and encodes for fatty acid ω-hydroxylase of both saturated and unsaturated fatty acids. The CYP4V2 protein is localized most abundantly within the endoplasmic reticulum in the RPE and is postulated to play a role in the physiological lipid recycling system between the RPE and photoreceptors to maintain visual function. Electroretinographic assessments have revealed progressive dysfunction of rod and cone photoreceptors in patients with BCD. Several genotypes have been associated with more severe phenotypes based on clinical and electrophysiological findings. With the advent of multimodal imaging with spectral domain optical coherence tomography, fundus autofluorescence, and adaptive optics scanning laser ophthalmoscopy, more precise delineation of BCD severity and progression is now possible, allowing for the potential future development of targets for gene therapy. PMID:27228076

  20. Congenital neurogenic muscular atrophy in megaconial myopathy due to a mutation in CHKB gene.

    PubMed

    Castro-Gago, Manuel; Dacruz-Alvarez, David; Pintos-Martínez, Elena; Beiras-Iglesias, Andrés; Arenas, Joaquín; Martín, Miguel Ángel; Martínez-Azorín, Francisco

    2016-01-01

    Choline kinase beta gene (CHKB) mutations have been identified in Megaconial Congenital Muscular Dystrophy (MDCMC) patients, a very rare inborn error of metabolism with 21 cases reported worldwide. We report the case of a Spanish boy of Caucasian origin who presented a generalized congenital muscular hypotonia, more intense at lower limb muscles, mildly elevated creatine kinase (CK), serum aspartate transaminase (AST) and lactate. Electromyography (EMG) showed neurogenic potentials in the proximal muscles. Histological studies of a muscle biopsy showed neurogenic atrophy with enlarged mitochondria in the periphery of the fibers, and complex I deficiency. Finally, genetic analysis showed the presence of a homozygous mutation in the gene for choline kinase beta (CHKB: NM_005198.4:c.810T>A, p.Tyr270(∗)). We describe here the second Spanish patient whit mutation in CHKB gene, who despite having the same mutation, presented an atypical aspect: congenital neurogenic muscular atrophy progressing to a combined neuropathic and myopathic phenotype (mixed pattern).

  1. Recessive RYR1 mutations in a patient with severe congenital nemaline myopathy with ophthalomoplegia identified through massively parallel sequencing.

    PubMed

    Kondo, Eri; Nishimura, Takafumi; Kosho, Tomoki; Inaba, Yuji; Mitsuhashi, Satomi; Ishida, Takefumi; Baba, Atsushi; Koike, Kenichi; Nishino, Ichizo; Nonaka, Ikuya; Furukawa, Toru; Saito, Kayoko

    2012-04-01

    Nemaline myopathy (NM) is a group of congenital myopathies, characterized by the presence of distinct rod-like inclusions "nemaline bodies" in the sarcoplasm of skeletal muscle fibers. To date, ACTA1, NEB, TPM3, TPM2, TNNT1, and CFL2 have been found to cause NM. We have identified recessive RYR1 mutations in a patient with severe congenital NM, through high-throughput screening of congenital myopathy/muscular dystrophy-related genes using massively parallel sequencing with target gene capture. The patient manifested fetal akinesia, neonatal severe hypotonia with muscle weakness, respiratory insufficiency, swallowing disturbance, and ophthalomoplegia. Skeletal muscle histology demonstrated nemaline bodies and small type 1 fibers, but without central cores or minicores. Congenital myopathies, a molecularly, histopathologically, and clinically heterogeneous group of disorders are considered to be a good candidate for massively parallel sequencing. PMID:22407809

  2. Congenital lobar emphysema

    PubMed Central

    Tural-Kara, Tuğçe; Özdemir, Halil; Çiftçi, Ergin; İnce, Erdal

    2016-01-01

    Congenital lobar emphysema is a rare disease, which is characterized by pulmoner hyperinflation. Depending on the degree of bronchial obstruction, the clinical presentation may be variable. We report a rare case with congenital lobar emphysema in a 38-days-old male infant who presented with severe respiratory distress and hypertension. Air trapping in the left upper lung and significant mediastinal shift to the right were observed on the chest x-ray. Emphysematous changes were detected on the thorax computed tomography and considered as congenital lobar emphysema. The upper left lobectomy was successfully performed by pediatric surgeons. On postoperative follow up, no sign of respiratory distress occurred and the patient was normotensive. In this report, a case with congenital lobar emphysema, which is a rare cause of respiratory distress and hypertension is discussed. PMID:27381542

  3. Giant congenital nevus

    MedlinePlus

    ... pigmented nevus; Giant hairy nevus; Giant pigmented nevus; Bathing trunk nevus; Congenital melanocytic nevus - large ... baby grows in the womb. In some families bathing trunk nevi may be inherited. The condition may ...

  4. Adult Congenital Heart Association

    MedlinePlus

    ... survivable, manageable, yet in the routine years between infancy and adulthood, sometimes forgettable. The Adult Congenital Heart ... understand the continuum of the disease from its infancy. The Adult Congential Heart Association brings together valuable ...

  5. Congenital nephrotic syndrome

    MedlinePlus

    ... may be high. There may be signs of malnutrition. A urinalysis reveals fat and large amounts of ... The disorder often leads to infection, malnutrition, and kidney failure. ... die within the first year. Congenital nephrotic syndrome ...

  6. Congenital platelet function defects

    MedlinePlus

    Platelet storage pool disorder; Glanzmann's thrombasthenia; Bernard-Soulier syndrome; Platelet function defects - congenital ... disorder may also cause severe bleeding. Platelet storage pool disorder (also called platelet secretion disorder) occurs when ...

  7. Congenital heart disease

    MedlinePlus

    ... about genetic counseling and screening if you have a family history of cogenital heart disease. ... Fraser CD, Carberry KE. Congenital heart disease. In: Townsend CM ... Textbook of Cardiovascular Medicine . 10th ed. Philadelphia, PA: ...

  8. Advances in gene therapy for muscular dystrophies

    PubMed Central

    Abdul-Razak, Hayder; Malerba, Alberto; Dickson, George

    2016-01-01

    Duchenne muscular dystrophy (DMD) is a recessive lethal inherited muscular dystrophy caused by mutations in the gene encoding dystrophin, a protein required for muscle fibre integrity. So far, many approaches have been tested from the traditional gene addition to newer advanced approaches based on manipulation of the cellular machinery either at the gene transcription, mRNA processing or translation levels. Unfortunately, despite all these efforts, no efficient treatments for DMD are currently available. In this review, we highlight the most advanced therapeutic strategies under investigation as potential DMD treatments.

  9. Advances in gene therapy for muscular dystrophies

    PubMed Central

    Abdul-Razak, Hayder; Malerba, Alberto; Dickson, George

    2016-01-01

    Duchenne muscular dystrophy (DMD) is a recessive lethal inherited muscular dystrophy caused by mutations in the gene encoding dystrophin, a protein required for muscle fibre integrity. So far, many approaches have been tested from the traditional gene addition to newer advanced approaches based on manipulation of the cellular machinery either at the gene transcription, mRNA processing or translation levels. Unfortunately, despite all these efforts, no efficient treatments for DMD are currently available. In this review, we highlight the most advanced therapeutic strategies under investigation as potential DMD treatments. PMID:27594988

  10. Dystroglycan induced muscular dystrophies - a review.

    PubMed

    Zhang, Q-Z

    2016-09-01

    Dystroglycanopathies are muscular dystrophies caused by mutations in genes involved the in O-linked glycosylation of α-dystroglycan. Severe forms of these conditions result in abnormalities in exhibit brain and ocular developmental too, in addition to muscular dystrophy. The full spectrum of developmental pathology is caused mainly by loss of dystroglycan from Bergmann glia. Moreover, cognitive deficits are constant features of severe forms of dystroglycanopathies. However, the precise molecular mechanism leading to neuronal dysfunction in these diseases is not fully known yet. The present review article will discuss the importance of dystroglycan in cerebellar development and associated pathological states. PMID:27649671

  11. Advances in gene therapy for muscular dystrophies.

    PubMed

    Abdul-Razak, Hayder; Malerba, Alberto; Dickson, George

    2016-01-01

    Duchenne muscular dystrophy (DMD) is a recessive lethal inherited muscular dystrophy caused by mutations in the gene encoding dystrophin, a protein required for muscle fibre integrity. So far, many approaches have been tested from the traditional gene addition to newer advanced approaches based on manipulation of the cellular machinery either at the gene transcription, mRNA processing or translation levels. Unfortunately, despite all these efforts, no efficient treatments for DMD are currently available. In this review, we highlight the most advanced therapeutic strategies under investigation as potential DMD treatments. PMID:27594988

  12. The IC3D Classification of the Corneal Dystrophies

    PubMed Central

    Weiss, Jayne S.; Møller, H. U.; Lisch, Walter; Kinoshita, Shigeru; Aldave, Anthony J.; Belin, Michael W.; Kivelä, Tero; Busin, Massimo; Munier, Francis L.; Seitz, Berthold; Sutphin, John; Bredrup, Cecilie; Mannis, Mark J.; Rapuano, Christopher J.; Van Rij, Gabriel; Kim, Eung Kweon; Klintworth, Gordon K.

    2010-01-01

    Background The recent availability of genetic analyses has demonstrated the shortcomings of the current phenotypic method of corneal dystrophy classification. Abnormalities in different genes can cause a single phenotype, whereas different defects in a single gene can cause different phenotypes. Some disorders termed corneal dystrophies do not appear to have a genetic basis. Purpose The purpose of this study was to develop a new classification system for corneal dystrophies, integrating up-to-date information on phenotypic description, pathologic examination, and genetic analysis. Methods The International Committee for Classification of Corneal Dystrophies (IC3D) was created to devise a current and accurate nomenclature. Results This anatomic classification continues to organize dystrophies according to the level chiefly affected. Each dystrophy has a template summarizing genetic, clinical, and pathologic information. A category number from 1 through 4 is assigned, reflecting the level of evidence supporting the existence of a given dystrophy. The most defined dystrophies belong to category 1 (a well-defined corneal dystrophy in which a gene has been mapped and identified and specific mutations are known) and the least defined belong to category 4 (a suspected dystrophy where the clinical and genetic evidence is not yet convincing). The nomenclature may be updated over time as new information regarding the dystrophies becomes available. Conclusions The IC3D Classification of Corneal Dystrophies is a new classification system that incorporates many aspects of the traditional definitions of corneal dystrophies with new genetic, clinical, and pathologic information. Standardized templates provide key information that includes a level of evidence for there being a corneal dystrophy. The system is user-friendly and upgradeable and can be retrieved on the website www.corneasociety.org/ic3d. PMID:19337156

  13. Distal Myopathies: Case Studies.

    PubMed

    Shaibani, Aziz

    2016-08-01

    About 15% of myopathies present with distal weakness. Lack of sensory deficit, and preservation of sensory responses and deep tendon reflexes, favors a myopathic cause for distal weakness. Electromyogram confirms this diagnosis. Profuse spontaneous discharges are common in inflammatory, metabolic, and myofibrillar myopathy (MFM). If the clinical picture indicates a specific disease such as facioscapulohumeral muscular dystrophy (FSHD), genetic testing provides the quickest diagnosis. Otherwise, muscle biopsy can distinguish specific features. The common causes of myopathic distal weakness are FSHD, myotonic dystrophy, and inclusion body myositis. Other causes include MFM, distal muscular dystrophies, metabolic myopathies, and congenital myopathies. PMID:27445241

  14. Cardiomyopathy in becker muscular dystrophy: Overview

    PubMed Central

    Ho, Rady; Nguyen, My-Le; Mather, Paul

    2016-01-01

    Becker muscular dystrophy (BMD) is an X-linked recessive disorder involving mutations of the dystrophin gene. Cardiac involvement in BMD has been described and cardiomyopathy represents the number one cause of death in these patients. In this paper, the pathophysiology, clinical evaluations and management of cardiomyopathy in patients with BMD will be discussed. PMID:27354892

  15. Genetics Home Reference: facioscapulohumeral muscular dystrophy

    MedlinePlus

    ... Padberg GW, Lunt PW, van der Maarel SM. Best practice guidelines on genetic diagnostics of Facioscapulohumeral muscular dystrophy: ... Reviewed : August 2014 Published : August 30, 2016 The resources on this site should not be used as a ... of Health & Human Services National Institutes of Health National Library of ...

  16. Visuospatial Attention Disturbance in Duchenne Muscular Dystrophy

    ERIC Educational Resources Information Center

    De Moura, Maria Clara Drummond Soares; do Valle, Luiz Eduardo Ribeiro; Resende, Maria Bernadete Dutra; Pinto, Katia Osternack

    2010-01-01

    Aim: The cognitive deficits present in the Duchenne muscular dystrophy (DMD) are not yet well characterized. Attention, considered to be the brain mechanism responsible for the selection of sensory stimuli, could be disturbed in DMD, contributing, at least partially, to the observed global cognitive deficit. The aim of this study was to…

  17. Genetics of Congenital Cataract.

    PubMed

    Pichi, Francesco; Lembo, Andrea; Serafino, Massimiliano; Nucci, Paolo

    2016-01-01

    Congenital cataract is a type of cataract that presents at birth or during early childhood, and it is one of the most easily treatable causes of visual impairment and blindness during infancy, with an estimated prevalence of 1-6 cases per 10,000 live births. Approximately 50% of all congenital cataract cases may have a genetic cause, and such cases are quite heterogeneous. Although congenital nuclear cataract can be caused by multiple factors, genetic mutation remains the most common cause. All three types of Mendelian inheritance have been reported for cataract; however, autosomal dominant transmission seems to be the most frequent. The transparency and high refractive index of the lens are achieved by the precise architecture of fiber cells and homeostasis of the lens proteins in terms of their concentrations, stabilities, and supramolecular organization. Research on hereditary congenital cataract has led to the identification of several classes of candidate genes that encode proteins such crystallins, lens-specific connexins, aquaporin, cytoskeletal structural proteins, and developmental regulators. In this review, we highlight the identified genetic mutations that account for congenital nuclear cataract.

  18. Congenital Vascular Anomalies.

    PubMed

    Gravereaux, Edwin C.; Nguyen, Louis L.; Cunningham, Leslie D.

    2004-04-01

    Congenital vascular anomalies are rare. The cardiovascular specialist should nevertheless be aware of the more common types of vascular anomalies and understand the implications for patient treatment and the likelihood of associated morbidity. The presentation of congenital arteriovenous malformations can range from asymptomatic or cosmetic lesions, to those causing ischemia, ulceration, hemorrhage, or high-output congestive heart failure. Treatment of large, symptomatic arteriovenous malformations often requires catheter-directed embolization prior to the attempt at complete surgical excision. Later recurrence, due to collateral recruitment, is frequent. Graded compression stockings and leg elevation are the mainstays of treatment for the predominantly venous congenital vascular anomalies. Most congenital central venous disorders are clinically silent. An exception is the retrocaval ureter. Retroaortic left renal vein, circumaortic venous ring, and absent, left-sided or duplicated inferior vena cava are relevant when aortic or inferior vena cava procedures are planned. The treatment of the venous disorders is directed at prevention or management of symptoms. Persistent sciatic artery, popliteal entrapment syndrome, and aberrant right subclavian artery origin are congenital anomalies that are typically symptomatic at presentation. Because they mimic more common diseases, diagnosis is frequently delayed. Delay can result in significant morbidity for the patient. Failure to make the diagnosis of persistent sciatic artery and popliteal entrapment can result in critical limb ischemia and subsequent amputation. Unrecognized aberrant right subclavian artery origin associated with aneurysmal degeneration can rupture and result in death. The treatment options for large-vessel arterial anomalies are surgical, sometimes in combination with endovascular techniques.

  19. Adults with Congenital Heart Defects

    MedlinePlus

    ... Pressure High Blood Pressure Tools & Resources Stroke More Web Booklet: Adults With Congenital Heart Defects Updated:Apr ... topic from the list below to learn more. Web Booklet: Adults With Congenital Heart Defects Introduction Introduction: ...

  20. Congenital tracheobronchial stenosis.

    PubMed

    Hewitt, Richard J; Butler, Colin R; Maughan, Elizabeth F; Elliott, Martin J

    2016-06-01

    Congenital tracheobronchial stenosis is a rare disease characterized by complete tracheal rings that can affect variable lengths of the tracheobronchial tree. It causes high levels of morbidity and mortality both due to the stenosis itself and to the high incidence of other associated congenital malformations. Successful management of this complex condition requires a highly individualized approach delivered by an experienced multidisciplinary team, which is best delivered within centralized units with the necessary diverse expertise. In such settings, surgical correction by slide tracheoplasty has become increasingly successful over the past 2 decades such that long-term survival now exceeds 88%, with normalization of quality of life scores for patients with non-syndrome-associated congenital tracheal stenosis. Careful assessment and planning of treatment strategies is of paramount importance for both successful management and the provision of patients and carers with accurate and realistic treatment counseling. PMID:27301600

  1. Genetic testing for retinal dystrophies and dysfunctions: benefits, dilemmas and solutions.

    PubMed

    Koenekoop, Robert K; Lopez, Irma; den Hollander, Anneke I; Allikmets, Rando; Cremers, Frans P M

    2007-07-01

    Human retinal dystrophies have unparalleled genetic and clinical diversity and are currently linked to more than 185 genetic loci. Genotyping is a crucial exercise, as human gene-specific clinical trials to study photoreceptor rescue are on their way. Testing confirms the diagnosis at the molecular level and allows for a more precise prognosis of the possible future clinical evolution. As treatments are gene-specific and the 'window of opportunity' is time-sensitive; accurate, rapid and cost-effective genetic testing will play an ever-increasing crucial role. The gold standard is sequencing but is fraught with excessive costs, time, manpower issues and finding non-pathogenic variants. Therefore, no centre offers testing of all currently 132 known genes. Several new micro-array technologies have emerged recently, that offer rapid, cost-effective and accurate genotyping. The new disease chips from Asper Ophthalmics (for Stargardt dystrophy, Leber congenital amaurosis [LCA], Usher syndromes and retinitis pigmentosa) offer an excellent first pass opportunity. All known mutations are placed on the chip and in 4 h a patient's DNA is screened. Identification rates (identifying at least one disease-associated mutation) are currently approximately 70% (Stargardt), approximately 60-70% (LCA) and approximately 45% (Usher syndrome subtype 1). This may be combined with genotype-phenotype correlations that suggest the causal gene from the clinical appearance (e.g. preserved para-arteriolar retinal pigment epithelium suggests the involvement of the CRB1 gene in LCA). As approximately 50% of the retinal dystrophy genes still await discovery, these technologies will improve dramatically as additional novel mutations are added. Genetic testing will then become standard practice to complement the ophthalmic evaluation. PMID:17651254

  2. Phase 3 Study of Ataluren in Patients With Nonsense Mutation Duchenne Muscular Dystrophy

    ClinicalTrials.gov

    2016-08-02

    Muscular Dystrophy, Duchenne; Muscular Dystrophies; Muscular Disorders, Atrophic; Muscular Diseases; Musculoskeletal Diseases; Neuromuscular Diseases; Nervous System Diseases; Genetic Diseases, X-Linked; Genetic Diseases, Inborn

  3. Muscular dystrophy in a dish: engineered human skeletal muscle mimetics for disease modeling and drug discovery.

    PubMed

    Smith, Alec S T; Davis, Jennifer; Lee, Gabsang; Mack, David L; Kim, Deok-Ho

    2016-09-01

    Engineered in vitro models using human cells, particularly patient-derived induced pluripotent stem cells (iPSCs), offer a potential solution to issues associated with the use of animals for studying disease pathology and drug efficacy. Given the prevalence of muscle diseases in human populations, an engineered tissue model of human skeletal muscle could provide a biologically accurate platform to study basic muscle physiology, disease progression, and drug efficacy and/or toxicity. Such platforms could be used as phenotypic drug screens to identify compounds capable of alleviating or reversing congenital myopathies, such as Duchene muscular dystrophy (DMD). Here, we review current skeletal muscle modeling technologies with a specific focus on efforts to generate biomimetic systems for investigating the pathophysiology of dystrophic muscle. PMID:27109386

  4. Congenital muscular torticollis.

    PubMed

    Nilesh, Kumar; Mukherji, Srijon

    2013-07-01

    Congenital muscular torticollis (CMT) is a rare congenital musculoskeletal disorder characterized by unilateral shortening of the sternocleidomastoid muscle (SCM). It presents in newborn infants or young children with reported incidence ranging from 0.3% to 2%. Owing to effective shortening of SCM on the involved side there is ipsilateral head tilt and contralateral rotation of the face and chin. This article reports a case of CMT in a 3½-year-old male child successfully managed by surgical release of the involved SCM followed by physiotherapy.

  5. Congenital muscular torticollis

    PubMed Central

    Nilesh, Kumar; Mukherji, Srijon

    2013-01-01

    Congenital muscular torticollis (CMT) is a rare congenital musculoskeletal disorder characterized by unilateral shortening of the sternocleidomastoid muscle (SCM). It presents in newborn infants or young children with reported incidence ranging from 0.3% to 2%. Owing to effective shortening of SCM on the involved side there is ipsilateral head tilt and contralateral rotation of the face and chin. This article reports a case of CMT in a 3½-year-old male child successfully managed by surgical release of the involved SCM followed by physiotherapy. PMID:24205484

  6. Congenital Adrenal Hyperplasia

    PubMed Central

    Speiser, Phyllis W.

    2015-01-01

    Congenital adrenal hyperplasia associated with deficiency of steroid 21-hydroxylase is the most common inborn error in adrenal function and the most common cause of adrenal insufficiency in the pediatric age group. As patients now survive into adulthood, adult health-care providers must also be familiar with this condition. Over the past several years, F1000 has published numerous commentaries updating research and practical guidelines for this condition. The purposes of this review are to summarize basic information defining congenital adrenal hyperplasia and to highlight current knowledge and controversies in management. PMID:26339484

  7. The involvement of collagen triple helix repeat containing 1 in muscular dystrophies.

    PubMed

    Spector, Itai; Zilberstein, Yael; Lavy, Adi; Genin, Olga; Barzilai-Tutsch, Hila; Bodanovsky, Ana; Halevy, Orna; Pines, Mark

    2013-03-01

    Fibrosis is the main complication of muscular dystrophies. We identified collagen triple helix repeat containing 1 (Cthrc1) in skeletal and cardiac muscles of mice, representing Duchenne and congenital muscle dystrophies (DMD and CMD, respectively), and dysferlinopathy. In all of the mice, Cthrc1 was associated with high collagen type I levels; no Cthrc1 or collagen was observed in muscles of control mice. High levels of Cthrc1 were also observed in biopsy specimens from patients with DMD, in whom they were reversibly correlated with that of β-dystroglycan, whereas collagen type I levels were elevated in all patients with DMD. At the muscle sites where collagen and Cthrc1 were adjacent, collagen fibers appeared smaller, suggesting involvement of Cthrc1 in collagen turnover. Halofuginone, an inhibitor of Smad3 phosphorylation downstream of the transforming growth factor-β signaling, reduced Cthrc1 levels in skeletal and cardiac muscles of mice, representing DMD, CMD, and dysferlinopathy. The myofibroblasts infiltrating the dystrophic muscles of the murine models of DMD, CMD, and dysferlinopathy were the source of Cthrc1. Transforming growth factor-β did not affect Cthrc1 levels in the mdx fibroblasts but decreased them in the control fibroblasts, in association with increased migration of mdx fibroblasts and dystrophic muscle invasion by myofibroblasts. To our knowledge, this is the first demonstration of Cthrc1 as a marker of the severity of the disease progression in the dystrophic muscles, and as a possible target for therapy.

  8. [Herpetiform bilateral epithelial corneal dystrophy caused by Tyrosinemia (Richner-Hanhart-Syndrome) (author's transl)].

    PubMed

    Jaeger, W; Gallasch, G; Schnyder, U W; Lutz, P; Schmidt, H

    1978-10-01

    Nutritional Tyrosinemia in animal experiments (Schweizer, Burns a. o.) caused an epithelial corneal dystrophy. The corresponding clinical picture is the Richner-Hanhart-Syndrome with herpetiform epithelial corneal dystrophy, palmo-plantar-keratosis and -- in some case -- a later developing oligophrenia. Goldsmith and coworkers suceeded to find out that all these symptoms are combined with tyrosinemia presumably caused ty one congenital enzyme defect. -- Personal clinical observations of such patients demonstrate that as well the corneal as the dermatological symptoms could be cured by diet, if the diagnosis is made in childhood. Corneal symptoms are still absent with a tyrosinemia as high as 10 mg%. Dietetic formula was found out to maintain this level, which is low enough to avoid the symptoms of Richner-Hanhart-Syndrome and certainly high enough to avoid symptoms of nutritional deficiency. One might expect that oligophrenia will not develop if this diet is used consequently. -- Since the first corneal symptoms develop already during the first years of life the ophthalmologist ought to know this etiology. The levels of tyrosinemia are so exorbitant (30--50 mg%) that the laboratory diagnosis is possible without any difficulty. If the diagnosis is only made in adult patients dietetic therapy is of limited value.

  9. An unusual central retinal dystrophy associated with ichthyosis vulgaris.

    PubMed

    Saatci, O A; Ozbek, Z; Köse, S; Durak, I; Kavukçu, S

    2000-06-01

    A number of ichthyosis syndromes may have retinal abnormalities such as the retinitis pigmentosa-like diffuse rod-cone dystrophy in Refsum's syndrome and the maculopathy in Sjögren-Larsson syndrome. We present two sisters who have an unusual, almost identical, bilaterally symmetric central retinal dystrophy associated with ichthyosis vulgaris in the absence of other systemic disorders. We believe that this dystrophy has not been previously described in patients with any of the known varieties of ichthyosis.

  10. B4GALNT2 (GALGT2) Gene Therapy Reduces Skeletal Muscle Pathology in the FKRP P448L Mouse Model of Limb Girdle Muscular Dystrophy 2I.

    PubMed

    Thomas, Paul J; Xu, Rui; Martin, Paul T

    2016-09-01

    Overexpression of B4GALNT2 (previously GALGT2) inhibits the development of muscle pathology in mouse models of Duchenne muscular dystrophy, congenital muscular dystrophy 1A, and limb girdle muscular dystrophy 2D. In these models, muscle GALGT2 overexpression induces the glycosylation of α dystroglycan with the cytotoxic T cell glycan and increases the overexpression of dystrophin and laminin α2 surrogates known to inhibit disease. Here, we show that GALGT2 gene therapy significantly reduces muscle pathology in FKRP P448Lneo(-) mice, a model for limb girdle muscular dystrophy 2I. rAAVrh74.MCK.GALGT2-treated FKRP P448Lneo(-) muscles showed reduced levels of centrally nucleated myofibers, reduced variance, increased size of myofiber diameters, reduced myofiber immunoglobulin G uptake, and reduced muscle wasting at 3 and 6 months after treatment. GALGT2 overexpression in FKRP P448Lneo(-) muscles did not cause substantial glycosylation of α dystroglycan with the cytotoxic T cell glycan or increased expression of dystrophin and laminin α2 surrogates in mature skeletal myofibers, but it increased the number of embryonic myosin-positive regenerating myofibers. These data demonstrate that GALGT2 overexpression can reduce the extent of muscle pathology in FKRP mutant muscles, but that it may do so via a mechanism that differs from its ability to induce surrogate gene expression. PMID:27561302

  11. B4GALNT2 (GALGT2) Gene Therapy Reduces Skeletal Muscle Pathology in the FKRP P448L Mouse Model of Limb Girdle Muscular Dystrophy 2I.

    PubMed

    Thomas, Paul J; Xu, Rui; Martin, Paul T

    2016-09-01

    Overexpression of B4GALNT2 (previously GALGT2) inhibits the development of muscle pathology in mouse models of Duchenne muscular dystrophy, congenital muscular dystrophy 1A, and limb girdle muscular dystrophy 2D. In these models, muscle GALGT2 overexpression induces the glycosylation of α dystroglycan with the cytotoxic T cell glycan and increases the overexpression of dystrophin and laminin α2 surrogates known to inhibit disease. Here, we show that GALGT2 gene therapy significantly reduces muscle pathology in FKRP P448Lneo(-) mice, a model for limb girdle muscular dystrophy 2I. rAAVrh74.MCK.GALGT2-treated FKRP P448Lneo(-) muscles showed reduced levels of centrally nucleated myofibers, reduced variance, increased size of myofiber diameters, reduced myofiber immunoglobulin G uptake, and reduced muscle wasting at 3 and 6 months after treatment. GALGT2 overexpression in FKRP P448Lneo(-) muscles did not cause substantial glycosylation of α dystroglycan with the cytotoxic T cell glycan or increased expression of dystrophin and laminin α2 surrogates in mature skeletal myofibers, but it increased the number of embryonic myosin-positive regenerating myofibers. These data demonstrate that GALGT2 overexpression can reduce the extent of muscle pathology in FKRP mutant muscles, but that it may do so via a mechanism that differs from its ability to induce surrogate gene expression.

  12. Cogan's microcystic dystrophy of the cornea: ultrastructure and photomicroscopy.

    PubMed Central

    Dark, A J

    1978-01-01

    Corneal biopsy specimens from 3 patients with Cogan's microcystic corneal dystrophy were examined by light and electron microscopy. Specimens were taken from corneas showing microcysts, geographic or map-like areas, and refractile striae. In all samples there is a bilaminate subepithelial layer of fibrogranular material, the friability of which is probably the basis for recurrent erosions in this disorder. Histochemical and ultrastructural findings provide further evidence that Cogan's dystrophy, the finger print/bleb dystrophy, and Meesmann's dystrophy should be regarded as separate entities. Images PMID:310689

  13. The congenital cranial dysinnervation disorders.

    PubMed

    Gutowski, N J; Chilton, J K

    2015-07-01

    Congenital cranial dysinnervation disorders (CCDD) encompass a number of related conditions and includes Duane syndrome, congenital fibrosis of the external ocular muscles, Möbius syndrome, congenital ptosis and hereditary congenital facial paresis. These are congenital disorders where the primary findings are non-progressive and are caused by developmental abnormalities of cranial nerves/nuclei with primary or secondary dysinnervation. Several CCDD genes have been found, which enhance our understanding of the mechanisms involved in brain stem development and axonal guidance. PMID:25633065

  14. Imaging of congenital pulmonary malformations.

    PubMed

    Praticò, Francesco Emanuele; Corrado, Michele; Della Casa, Giovanni; Parziale, Raffaele; Russo, Giuseppe; Gazzani, Silvia Eleonora; Rossi, Enrica; Borgia, Daniele; Mostardi, Maurizio; Bacchini, Emanuele; Cella, Simone; De Filippo, Massimo

    2016-01-01

    Congenital pulmonary malformations represent a broad spectrum of anomalies that may result in varied clinical and pathologic pictures, ranging from recurrent pulmonary infections and acute respiratory distress syndrome, which require timely drug therapy, up to large space-occupying lesions needing surgical treatment. This classification includes three distinct anatomical and pathological entities, represented by Congenital Cystic Adenomatoid Malformation, Bronchopulmonary Sequestration and Congenital Lobar Emphysema. The final result in terms of embryological and fetal development of these alterations is a Congenital Lung Hypoplasia. Since even Bronchial Atresia, Pulmonary Bronchogenic Cysts and Congenital Diaphragmatic Hernias are due to Pulmonary Hypoplasia, these diseases will be discussed in this review (1, 2). PMID:27467867

  15. [Diagnosis of congenital infection].

    PubMed

    Sampedro Martínez, Antonio; Martínez, Luis Aliaga; Teatino, Pablo Mazuelas; Rodríguez-Granger, Javier

    2011-12-01

    In general, congenital diagnosis is based on: a) maternal serologic assays; b) microbiologic study of amniotic fluid or fetal blood sampling; and c) serology in children and microorganism detection by polymerase chain reaction (PCR) or culture. Congenital infections due to cytomegalovirus, herpes simplex, varicella, B19 erythrovirus and toxoplasmosis are usually the result of primary infection in the mother. Therefore, when IgG antibodies are detected before pregnancy, these infections are ruled out. Definitive serologic diagnosis of acute infection in pregnant women requires the demonstration of seroconversion (i.e., from seronegative to seropositive). In these cases, amniotic fluid or fetal blood sampling should be performed to determine the presence of intrauterine congenital infection. Cytomegalovirus, rubella and toxoplasmosis can be diagnosed by detection of specific IgM antibodies in fetal blood. However, PCR in amniotic fluid has replaced conventional prenatal diagnostic techniques, including fetal blood sampling, in the diagnosis of these infections. In the newborn, these infections may be confirmed by measuring IgM specific antibodies. B19 erythrovirus can be detected by PCR in amniotic fluid or fetal blood. Congenital varicella-zoster infection may be diagnosed on the basis of persistence of IgG antibodies after birth. Definitive diagnosis of herpes simplex virus infection requires viral isolation. Swabs or scraping from clinical specimens can be inoculated into susceptible cell lines for isolation. PMID:22305665

  16. Congenital complete atrioventricular block.

    PubMed Central

    Kertesz, N J; Fenrich, A L; Friedman, R A

    1997-01-01

    Congenital complete atrioventricular block is found in 1 of 22,000 live births. Over time, it has become apparent that these patients represent not a single distinct disease process, but several processes with the common manifestation of atrioventricular block. The evaluation of these patients to determine their risk of sudden death and need for pacing is not well defined. Images PMID:9456483

  17. Congenital Midline Cervical Cleft

    PubMed Central

    Villanueva-Meyer, Javier; Glastonbury, Christine; Marcovici, Peter

    2015-01-01

    Congenital midline cervical cleft is a rare anomaly that typically presents in the neonatal period as a thin suprasternal vertical band of erythematous skin with a nipple-like projection superiorly, which may exude fluid. We present the clinical and pathophysiologic features and the imaging findings of this uncommon, and rarely described entity in a newborn girl. PMID:25926928

  18. Congenital adrenal hyperplasia

    MedlinePlus

    ... or inappropriately). Congenital adrenal hyperplasia can affect both boys and girls. About 1 in 10,000 to 18,000 ... penis but normal testes Well-developed muscles Both boys and girls will be tall as children, but much shorter ...

  19. Congenital Heart Information Network

    MedlinePlus

    ... Barmash and Uwe Baemayr for The Congenital Heart Information Network Exempt organization under Section 501(c)3. Copyright ©1996 - 2016 C.H.I.N. All rights reserved TX4-390-685 Original site design and HTML by Panoptic Communications

  20. Autism and Congenital Blindness.

    ERIC Educational Resources Information Center

    Hobson, R. Peter; Lee, Anthony; Brown, Rachel

    1999-01-01

    This study compared a group of nine children (ages 3 to 8) with congenital blindness and an autism-like syndrome with nine sighted children. Children with autism had more severe abnormalities in terms of their relationships with people and emotional expressions, and were more impaired in the area of pretend play. (CR)

  1. Multiple congenital coagulation deficiencies.

    PubMed

    BONNIN, J A; HICKS, N D; INNIS, M D; SIMPSON, D A

    1960-07-01

    A 6-week-old infant is presented who suffered from a congenital haemorrhagic disorder which caused death from subdural haemorrhage following mild trauma. Haematological investigation revealed deficiencies of factor VII and Christmas factor. Prower-Stuart factor was probably also deficient although investigation of this clotting factor was carried out only on serum obtained at necropsy.

  2. Reflex sympathetic dystrophy associated with antiepileptic drugs.

    PubMed

    Falasca, G F; Toly, T M; Reginato, A J; Schraeder, P L; O'Connor, C R

    1994-01-01

    Reflex sympathetic dystrophy syndrome (RSDS) complicating antiepileptic drug (AED) therapy is not well acknowledged in the neurologic literature. We report 4 patients with reflex sympathetic dystrophy that occurred while they were receiving AEDs. All patients had shoulder and hand involvement, which in 2 was bilateral, and 1 had ipsilateral foot involvement. Two patients did not respond to a change in AEDs, but all improved with a course of prednisone. One patient with phenobarbital (PB)-associated RSDS relapsed on inadvertent rechallenge with secobarbital. A review of the literature showed that several other fibrosing disorders are associated with AED administration, including Dupuytren's contractures, frozen shoulder, plantar and hand nodules, and Peyronie's disease. RSD associated with AEDs is important to recognize because it may result in permanent disability if treatment is delayed.

  3. Facioscapulohumeral dystrophy: case report and discussion.

    PubMed

    Castellano, Vincenzo; Feinberg, Joseph; Michaels, Jennifer

    2008-09-01

    Facioscapulohumeral dystrophy (FSHD) is often cited as the third most common form of muscular dystrophy. Therefore, it should be considered in patients with complaints of progressive weakness. We present the case of a man with facial, truncal, and leg weakness that initially sought medical attention for lower back pain. Electrodiagnostic testing revealed findings in the trapezius, serratus anterior, biceps, triceps, pectoralis major, tibialis anterior, and gastrocnemius muscles consistent with a myopathic disorder. Subsequent genetic testing identified a FSHD allele size consistent with a FSHD deletion mutation. Therefore, confirming the diagnosis of FSHD. Unfortunately, no effective treatments currently exist for FSHD. However, supportive measures involving physical therapy and the use of orthotics may aid in improving function and mobility. PMID:18815862

  4. Facioscapulohumeral Dystrophy: Case Report and Discussion

    PubMed Central

    Feinberg, Joseph; Michaels, Jennifer

    2008-01-01

    Facioscapulohumeral dystrophy (FSHD) is often cited as the third most common form of muscular dystrophy. Therefore, it should be considered in patients with complaints of progressive weakness. We present the case of a man with facial, truncal, and leg weakness that initially sought medical attention for lower back pain. Electrodiagnostic testing revealed findings in the trapezius, serratus anterior, biceps, triceps, pectoralis major, tibialis anterior, and gastrocnemius muscles consistent with a myopathic disorder. Subsequent genetic testing identified a FSHD allele size consistent with a FSHD deletion mutation. Therefore, confirming the diagnosis of FSHD. Unfortunately, no effective treatments currently exist for FSHD. However, supportive measures involving physical therapy and the use of orthotics may aid in improving function and mobility. PMID:18815862

  5. Limb Girdle Muscular Dystrophy (LGMD): Case Report

    PubMed Central

    Kalyan, Meenakshi; Gaikwad, Anu N.; Makadia, Ankit; Shah, Harshad

    2015-01-01

    We report a young male of autosomal recessive limb girdle muscular dystrophy (LGMD) with positive family history presented with gradual onset proximal muscle weakness in all four limbs since eight years and thinning of shoulders, arms and thighs. Neurological examination revealed atrophy of both shoulders with wasting of both deltoids thinning of thighs and pseudo hypertrophy of both calves, hypotonia in all four limbs. Gower’s sign was positive. Winging of scapula was present. Power was 3/5 at both shoulders, 4/5 at both elbows, 5/5 at both wrists, 3/5 at both hip joints, 3/5 at both knees, 5/5 at both ankles. All deep tendon reflexes and superficial reflexes were present with plantars bilateral flexors. Electromyography (EMG) showed myopathic pattern. He had elevated creatinine phosphokinase levels and muscle biopsy findings consistent with muscular dystrophy. PMID:25738022

  6. Dog Models for Blinding Inherited Retinal Dystrophies

    PubMed Central

    Komáromy, András M.

    2015-01-01

    Abstract Spontaneous canine models exist for several inherited retinal dystrophies. This review will summarize the models and indicate where they have been used in translational gene therapy trials. The RPE65 gene therapy trials to treat childhood blindness are a good example of how studies in dogs have contributed to therapy development. Outcomes in human clinical trials are compared and contrasted with the result of the preclinical dog trials. PMID:25671556

  7. Dog models for blinding inherited retinal dystrophies.

    PubMed

    Petersen-Jones, Simon M; Komáromy, András M

    2015-03-01

    Spontaneous canine models exist for several inherited retinal dystrophies. This review will summarize the models and indicate where they have been used in translational gene therapy trials. The RPE65 gene therapy trials to treat childhood blindness are a good example of how studies in dogs have contributed to therapy development. Outcomes in human clinical trials are compared and contrasted with the result of the preclinical dog trials.

  8. Dog models for blinding inherited retinal dystrophies.

    PubMed

    Petersen-Jones, Simon M; Komáromy, András M

    2015-03-01

    Spontaneous canine models exist for several inherited retinal dystrophies. This review will summarize the models and indicate where they have been used in translational gene therapy trials. The RPE65 gene therapy trials to treat childhood blindness are a good example of how studies in dogs have contributed to therapy development. Outcomes in human clinical trials are compared and contrasted with the result of the preclinical dog trials. PMID:25671556

  9. What Are the Types of Muscular Dystrophy?

    MedlinePlus

    ... means "present from birth." Congenital MD affects both boys and girls, who often require support to sit or stand ... lordosis (pronounced lawr-DOH-sis ) FSHD affects teen boys and girls typically but may occur as late as age ...

  10. Update on congenital glaucoma

    PubMed Central

    Mandal, Anil K; Chakrabarti, Debasis

    2011-01-01

    Congenital glaucoma is a global problem and poses a diagnostic and therapeutic challenge to the ophthalmologist. A detailed evaluation under general anesthesia is advisable to establish the diagnosis and plan for management. Medical therapy has a limited role and surgery remains the primary therapeutic modality. While goniotomy or trabeculotomy ab externo is valuable in the management of congenital glaucoma, primary combined trabeculotomy–trabeculectomy offers the best hope of success in advanced cases. Trabeculectomy with antifibrotic agent and glaucoma drainage devices has a role in the management of refractory cases, and cyclodestructive procedures should be reserved for patients where these procedures have failed. Early diagnosis, prompt therapeutic intervention and proper refractive correction are keys to success. Management of residual vision and visual rehabilitation should be an integral part of the management of children with low vision and lifelong follow-up is a must. PMID:21150027

  11. Congenital idiopathic clubfoot deformities.

    PubMed

    Kyzer, S P; Stark, S L

    1995-03-01

    Clubfoot is a birth defect that is marked primarily by a deformed talus (ie, ankle) and calcaneous (ie, heel) that give the foot a characteristic "club-like" appearance. In congenital idiopathic clubfoot (ie, talipes equinovarus), the infant's foot points downward (ie, equinus) and turns inward (ie, varus), while the forefoot curls toward the heel (ie, adduction). This congenital disorder has an incidence of 1 in 400 live births, with boys affected twice as often as girls. Unilateral clubfoot is somewhat more common than bilateral clubfoot and may occur as an isolated defect or in association with other disorders (eg, chromosomal aberrations, cerebral palsy, spina bifida, arthrogryposis). Infantile clubfoot deformity is painless and is correctable with early diagnosis and prompt treatment. PMID:7778903

  12. Congenital hemifacial hyperplasia.

    PubMed

    Deshingkar, S A; Barpande, S R; Bhavthankar, J D

    2011-07-01

    Congenital hemifacial hyperplasia (CHH) is a rare congenital malformation characterized by marked unilateral overdevelopment of hard and soft tissues of the face. Asymmetry in CHH is usually evident at birth and accentuated with age, especially at puberty. The affected side grows at a rate proportional to the nonaffected side so that the disproportion is maintained thr oughout the life. Multisystem involvement has resulted in etiological heterogeneity including heredity, chromosomal abnormalities, atypical forms of twinning, altered intrauterine environment, and endocrine dysfunctions; however, no single theory explains the etiology adequately. Deformities of all tissues of face, including teeth and their related tissues in the jaw, are key findings for correct diagnosis of CHH. Here an attempt has been made to present a case of CHH with its archetypal features and to supplement existing clinical knowledge. PMID:22090778

  13. Congenital lipodystrophies and dyslipidemias.

    PubMed

    Prieur, Xavier; Le May, Cedric; Magré, Jocelyne; Cariou, Bertrand

    2014-09-01

    Lipodystrophies are rare acquired and genetic disorders characterized by the selective loss of adipose tissue. One key metabolic feature of patients with congenital inherited lipodystrophy is hypertriglyceridemia. The precise mechanisms by which the lack of adipose tissue causes dyslipidemia remain largely unknown. In recent years, new insights have arisen from data obtained in vitro in adipocytes, yeast, drosophila, and very recently in several genetically modified mouse models of generalized lipodystrophy. A common metabolic pathway involving accelerated lipolysis and defective energy storage seems to contribute to the dyslipidemia associated with congenital generalized lipodystrophy syndromes, although the pathophysiological changes may vary with the nature of the mutation involved. Therapeutic management of dyslipidemia in patients with lipodystrophy is primarily based on specific approaches using recombinant leptin therapy. Preclinical studies suggest a potential efficacy of thiazolidinediones that remains to be assessed in dedicated clinical trials.

  14. Congenital hemifacial hyperplasia

    PubMed Central

    Deshingkar, S. A.; Barpande, S. R.; Bhavthankar, J. D.

    2011-01-01

    Congenital hemifacial hyperplasia (CHH) is a rare congenital malformation characterized by marked unilateral overdevelopment of hard and soft tissues of the face. Asymmetry in CHH is usually evident at birth and accentuated with age, especially at puberty. The affected side grows at a rate proportional to the nonaffected side so that the disproportion is maintained thr oughout the life. Multisystem involvement has resulted in etiological heterogeneity including heredity, chromosomal abnormalities, atypical forms of twinning, altered intrauterine environment, and endocrine dysfunctions; however, no single theory explains the etiology adequately. Deformities of all tissues of face, including teeth and their related tissues in the jaw, are key findings for correct diagnosis of CHH. Here an attempt has been made to present a case of CHH with its archetypal features and to supplement existing clinical knowledge. PMID:22090778

  15. Congenital brachymetatarsia: three cases.

    PubMed

    Ferrández, L; Yubero, J; Usabiaga, J; Ramos, L

    1993-01-01

    We report on three cases with congenital brachymetatarsia, one with bilateral affectation, together with the results of a lengthening of the short metatarsal bones by progressive axial distraction using an external minifixator. The method proved to be easy to implement, permitting immediate functionality of the ankle and early load bearing. The immediate results (cosmetic) and later findings (functional) were excellent in all three cases. PMID:8314189

  16. Congenital scoliosis - Quo vadis?

    PubMed

    Debnath, Ujjwal K; Goel, Vivek; Harshavardhana, Nanjanduppa; Webb, John K

    2010-04-01

    Congenital spinal vertebral anomalies can present as scoliosis or kyphosis or both. The worldwide prevalence of the vertebral anomalies is 0.5-1 per 1000 live births. Vertebral anomalies can range from hemi vertebrae (HV) which may be single or multiple, vertebral bar with or without HV, block vertebrae, wedge shaped or butterfly vertebrae. Seventy per cent of congenital vertebral anomalies result in progressive deformities. The risk factors for progression include: type of defect, site of defect (junctional regions) and patient's age at the time of diagnosis. The key to success in managing these spinal deformities is early diagnosis and anticipation of progression. One must intervene surgically to halt the progression of deformity and prevent further complications associated with progressive deformity. Planning for surgery includes a preoperative MRI scan to rule out spinal anomalies such as diastematomyelia. The goals of surgical treatment for congenital spinal deformity are to achieve a straight growing spine, a normal standing sagittal profile, and a short fusion segment. The options of surgery include in situ fusion, convex hemi epiphysiodesis and hemi vertebra excision. These basic surgical procedures can be combined with curve correction, instrumentation and short segment fusion. Most surgeons prefer posterior (only) surgery for uncomplicated HV excision and short segment fusion. These surgical procedures can be performed through posterior, anterior or combined approaches. The advocates of combined approaches suggest greater deformity correction possibilities with reduced incidence of pseudoarthrosis and minimize crankshaft phenomenon. We recommend posterior surgery for curves involving only an element of kyphosis or modest deformity, whereas combined anterior and posterior approach is indicated for large or lordotic deformities. In the last decade, the use of growing rods and vertebral expandable prosthetic titanium rib has improved the armamentarium of the

  17. Congenital Cataract Screening

    PubMed Central

    Rajavi, Zhale; Sabbaghi, Hamideh

    2016-01-01

    Congenital cataract is a leading cause of visual deprivation which can damage the developing visual system of a child; therefore early diagnosis, management and long-term follow-up are essential. It is recommended that all neonates be screened by red reflex examination at birth and suspected cases be referred to ophthalmic centers. Early surgery (<6 weeks of age, based on general neonatal health) is important for achieving the best visual outcome particularly in unilateral cases. In bilateral cases, surgery is highly recommended before appearance of strabismus or nystagmus (<10 weeks of age) with no longer than a one-week interval between the fellow eyes. Parents should be informed that surgery is a starting point and not the endpoint of treatment. Appropriate postoperative management including immediate optical correction in the form of aphakic glasses or contact lenses, or intraocular lens (IOL) implantation at the appropriate age (>1 year) is highly recommended. After surgery, amblyopia treatment and periodic follow-up examinations should be started as soon as possible to achieve a satisfactory visual outcome. Practitioners should consider the possibility of posterior capsular opacity, elevated intraocular pressure and amblyopia during follow-up, especially in eyes with microphthalmia and/or associated congenital anomalies. All strabismic children should undergo slit lamp examination prior to strabismus surgery to rule out congenital lens opacities. From a social point of view, equal and fair medical care should be provided to all children regardless of gender. PMID:27621790

  18. Congenital Cataract Screening

    PubMed Central

    Rajavi, Zhale; Sabbaghi, Hamideh

    2016-01-01

    Congenital cataract is a leading cause of visual deprivation which can damage the developing visual system of a child; therefore early diagnosis, management and long-term follow-up are essential. It is recommended that all neonates be screened by red reflex examination at birth and suspected cases be referred to ophthalmic centers. Early surgery (<6 weeks of age, based on general neonatal health) is important for achieving the best visual outcome particularly in unilateral cases. In bilateral cases, surgery is highly recommended before appearance of strabismus or nystagmus (<10 weeks of age) with no longer than a one-week interval between the fellow eyes. Parents should be informed that surgery is a starting point and not the endpoint of treatment. Appropriate postoperative management including immediate optical correction in the form of aphakic glasses or contact lenses, or intraocular lens (IOL) implantation at the appropriate age (>1 year) is highly recommended. After surgery, amblyopia treatment and periodic follow-up examinations should be started as soon as possible to achieve a satisfactory visual outcome. Practitioners should consider the possibility of posterior capsular opacity, elevated intraocular pressure and amblyopia during follow-up, especially in eyes with microphthalmia and/or associated congenital anomalies. All strabismic children should undergo slit lamp examination prior to strabismus surgery to rule out congenital lens opacities. From a social point of view, equal and fair medical care should be provided to all children regardless of gender.

  19. Congenital Cataract Screening.

    PubMed

    Rajavi, Zhale; Sabbaghi, Hamideh

    2016-01-01

    Congenital cataract is a leading cause of visual deprivation which can damage the developing visual system of a child; therefore early diagnosis, management and long-term follow-up are essential. It is recommended that all neonates be screened by red reflex examination at birth and suspected cases be referred to ophthalmic centers. Early surgery (<6 weeks of age, based on general neonatal health) is important for achieving the best visual outcome particularly in unilateral cases. In bilateral cases, surgery is highly recommended before appearance of strabismus or nystagmus (<10 weeks of age) with no longer than a one-week interval between the fellow eyes. Parents should be informed that surgery is a starting point and not the endpoint of treatment. Appropriate postoperative management including immediate optical correction in the form of aphakic glasses or contact lenses, or intraocular lens (IOL) implantation at the appropriate age (>1 year) is highly recommended. After surgery, amblyopia treatment and periodic follow-up examinations should be started as soon as possible to achieve a satisfactory visual outcome. Practitioners should consider the possibility of posterior capsular opacity, elevated intraocular pressure and amblyopia during follow-up, especially in eyes with microphthalmia and/or associated congenital anomalies. All strabismic children should undergo slit lamp examination prior to strabismus surgery to rule out congenital lens opacities. From a social point of view, equal and fair medical care should be provided to all children regardless of gender. PMID:27621790

  20. Congenital hemangiopericytoma: two case reports.

    PubMed

    Bosch, A M; Hack, W W; Ekkelkamp, S

    1998-03-01

    Congenital hemangiopericytoma is a rare tumor consisting of capillaries surrounded by pericytes. Only histologically can the tumor be distinguished from other vascular hamartomas. For a long time the congenital type was considered benign; however, metastases have recently been described. A histologic diagnosis of all soft-tissue sarcomas should be made. We describe two patients with congenital hemangiopericytomas in whom the diagnosis was not suspected until after histologic examination. Long-term follow-up is indicated.

  1. Congenital Dislocation of the Hip

    PubMed Central

    Premi, J. M.

    1976-01-01

    The implications of a diagnosis of congenital dislocation of the hip and the importance of the role of the family physician in early detection and treatment are identified. A review of the salient clinical features of congenital dislocation of the hip is undertaken. The results of a survey carried out in the author's practice on an unusual incidence of congenital dislocated hip are reviewed. PMID:21308053

  2. Radiology of congenital heart disease

    SciTech Connect

    Amplatz, K.

    1986-01-01

    This is a text on the radiologic diagnosis of congenital heart disease and its clinical manifestations. The main thrust of the book is the logical approach which allows an understanding of the complex theory of congenital heart disease. The atlas gives a concise overview of the entire field of congenital heart disease. Emphasis is placed on the understanding of the pathophysiology and its clinical and radiological consequences. Surgical treatment is included since it provides a different viewpoint of the anatomy.

  3. Severe congenital actin related myopathy with myofibrillar myopathy features.

    PubMed

    Selcen, Duygu

    2015-06-01

    Mutations in ACTA1 have been associated with different pathologic findings including nemaline myopathy, intranuclear rod myopathy, actin myopathy, cap myopathy, congenital fiber type disproportion, and core myopathy. Myofibrillar myopathies are morphologically distinct but genetically heterogeneous muscular dystrophies arising from mutations in Z-disk related proteins. We report a 26-month-old boy with significantly delayed motor development requiring mechanical ventilation and tube-feeding since birth. The muscle biopsy displayed typical features of myofibrillar myopathy with abnormal expression of multiple proteins. Whole exome sequencing revealed two-amino-acid duplication in ACTA1. In cell culture system, mutant actin was expressed at ~11% of wild-type, and mutant actin formed pleomorphic cytoplasmic aggregates whereas wild-type actin appeared in filamentous structures. We conclude that mutations in ACTA1 can cause pathologic features consistent with myofibrillar myopathy, and mutations in ACTA1 should be considered in patients with severe congenital hypotonia associated with muscle weakness and features of myofibrillar myopathy. PMID:25913210

  4. Congenital disorders of glycosylation with emphasis on cerebellar involvement.

    PubMed

    Barone, Rita; Fiumara, Agata; Jaeken, Jaak

    2014-07-01

    Congenital disorders of glycosylation (CDG) are genetic diseases due to defective glycosylation of proteins and lipids. The authors present an update on these disorders affecting the central nervous system with a focus on cerebellar involvement. The rate of identification of novel CDG shows an exponential increase. Some 76 CDG are actually known, not taking into account the defects in glycan-modifying proteins. Neurologic involvement is present in the large majority of CDG. Screening methods are limited to serum transferrin isoelectrofocusing (for N-glycosylation disorders with sialic acid deficiency), and serum apolipoprotein C-III isoelectrofocusing (for core 1 mucin-type O-glycosylation disorders). Whole exome/genome sequencing is increasingly used in the diagnostic workup of patients with CDG-X. Treatment is greatly lagging behind because only one CDG is efficiently treatable (MPI-CDG). Cerebellar involvement is an important feature of PMM2-CDG, the congenital muscular dystrophies due to dystroglycanopathy, and SRD5A3-CDG. It has also been reported in some patients with ALG1-CDG, ALG3-CDG, ALG9-CDG, ALG6-CDG, ALG8-CDG, PIGA-CDG, DPM1-CDG, DPM2-CDG, B4GALT1-CDG, SLC35A2-CDG, COG1-CDG, COG5-CDG, COG7-CDG, and COG8-CDG.

  5. Micropenis and congenital adrenal hypoplasia.

    PubMed

    Bourgeois, M J; Jones, B; Waagner, D C; Dunn, D

    1989-01-01

    Micropenis is often an early sign of congenital hypopituitarism. It has also been associated with congenital adrenal hypoplasia in infants with anencephaly and pituitary agenesis. This report is on two infants with micropenis and congenital adrenal hypoplasia. One presented with a similar clinical course and postmortem findings to previously reported cases of adrenal hypoplasia and pituitary agenesis. The other patient represents the first reported case of an infant with micropenis and congenital adrenal hypoplasia in the absence of pituitary agenesis. The histologic patterns of adrenal hypoplasia, as well as the etiologic and clinical implications of its association with micropenis, are discussed.

  6. Genetics Home Reference: congenital hepatic fibrosis

    MedlinePlus

    ... Home Health Conditions congenital hepatic fibrosis congenital hepatic fibrosis Enable Javascript to view the expand/collapse boxes. ... PDF Open All Close All Description Congenital hepatic fibrosis is a disease of the liver that is ...

  7. Genetics Home Reference: Leber congenital amaurosis

    MedlinePlus

    ... Registry: Leber congenital amaurosis 9 National Eye Institute: Gene Therapy for Leber Congenital Amaurosis These resources from MedlinePlus ... Additional NIH Resources (1 link) National Eye Institute: Gene Therapy for Leber Congenital Amaurosis Educational Resources (3 links) ...

  8. Noncoding RNAs: Emerging Players in Muscular Dystrophies

    PubMed Central

    2014-01-01

    The fascinating world of noncoding RNAs has recently come to light, thanks to the development of powerful sequencing technologies, revealing a variety of RNA molecules playing important regulatory functions in most, if not all, cellular processes. Many noncoding RNAs have been implicated in regulatory networks that are determinant for skeletal muscle differentiation and disease. In this review, we outline the noncoding RNAs involved in physiological mechanisms of myogenesis and those that appear dysregulated in muscle dystrophies, also discussing their potential use as disease biomarkers and therapeutic targets. PMID:24729974

  9. Perinatal and early infantile symptoms in congenital disorders of glycosylation.

    PubMed

    Funke, Simone; Gardeitchik, Thatjana; Kouwenberg, Dorus; Mohamed, Miski; Wortmann, Saskia B; Korsch, Eckhard; Adamowicz, Maciej; Al-Gazali, Lihadh; Wevers, Ron A; Horvath, Adrienne; Lefeber, Dirk J; Morava, Eva

    2013-03-01

    Congenital disorders of glycosylation (CDG) are a rapidly growing family of inborn errors. Screening for CDG in suspected cases is usually performed in the first year of life by serum transferrin isoelectric focusing or mass spectrometry. Based on the transferrin analysis patients can be biochemically diagnosed with a type 1 or type 2 transferrin pattern, and labeled as CDG-I, or CDG-II. The diagnosis of CDG is frequently delayed due to the highly variable phenotype, some cases showing single organ involvement and others mimicking syndromes, like skeletal dysplasia, cutis laxa syndrome, or congenital muscle dystrophy. The aim of our study was to evaluate perinatal abnormalities and early discriminative symptoms in 58 patients consecutively diagnosed with diverse CDG-subtypes. Neonatal findings and clinical features in the first months of life were studied in 36 children with CDG-I and 22 with CDG-II. Maternal complications were found in five, small for gestational age in nine patients. Five children had abnormal neonatal screening results for hypothyroidism. Congenital microcephaly and neonatal seizures were common in CDG-II. Inverted nipples were uncommon with 5 out of 58 children. Dysmorphic features were mostly nonspecific, except for cutis laxa. Early complications included feeding problems, cardiomyopathy, thrombosis, and bleeding. Cases presenting in the neonatal period had the highest mortality rate. Survival in CDG patients is highly dependent on early intervention therapy. We recommend low threshold screening for glycosylation disorders in infants with neurologic symptoms, even in the absence of abnormal fat distribution. Growth retardation and neonatal bleeding increase suspicion for CDG. PMID:23401092

  10. Congenital granular cell epulis.

    PubMed

    Conrad, Rachel; Perez, Mia C N

    2014-01-01

    Congenital granular cell epulis is a rarely reported lesion of unknown histogenesis with a strong predilection for the maxillary alveolar ridge of newborn girls. Microscopically, it demonstrates nests of polygonal cells with granular cytoplasm, a prominent capillary network, and attenuated overlying squamous epithelium. The lesion lacks immunoreactivity for S-100, laminin, chromogranin, and most other markers except neuron-specific enolase and vimentin. Through careful observation of its unique clinical, histopathologic, and immunohistochemical features, this lesion can be distinguished from the more common adult granular cell tumor as well as other differential diagnoses.

  11. Neonatal congenital microvillus atrophy

    PubMed Central

    Pecache, N; Patole, S; Hagan, R; Hill, D; Charles, A; Papadimitriou, J

    2004-01-01

    Congenital microvillous atrophy (CMVA) is the leading cause of neonatal secretory diarrhoea with onset either in the first 72 hours of life (early onset) or at 6–8 weeks after birth (late onset). To date over 30 cases have been reported worldwide. The prognosis for this life threatening condition continues to be poor. Therapeutic agents like somatostatin and epidermal growth factor are either ineffective or of marginal benefit. Overall five year survival after small bowel transplantation is currently ∼50%. The following brief review is aimed towards helping neonatologists/perinatologists in the early diagnosis, and management of CMVA and in counselling the parents appropriately. PMID:14970294

  12. [Congenital linear nevus sebaceus].

    PubMed

    Linnemann, Anders; Bygum, Anette; Fenger-Grøn, Jesper

    2011-09-01

    An unusual case of nevus sebaceous is described. Nevus sebaceous is a congenital epidermal hamartoma of the skin and the predilection site is the head or neck. In this case the nevus followed the lines of Blaschko along the back of the left lower extremity. The linear lesion seemed papulovesicular which caused suspicion of incontinentia pigmenti or infection, and the boy received antimicrobial treatment until a biopsy revealed the correct diagnosis. We wish to emphasize this clinical picture to spare the patient and relatives from unnecessary tests, treatment and concern. PMID:21893006

  13. Congenital anterior urethral diverticulum.

    PubMed

    Singh, Sanjeet Kumar; Ansari, Ms

    2014-09-01

    Congenital anterior urethral diverticulum (CAUD) may be found all along the anterior urethra and may present itself at any age, from infant to adult. Most children with this condition present with difficulty in initiating micturition, dribbling of urine, poor urinary stream, or urinary tract infection. A careful history will reveal that these children never had a good urinary stream since birth, and the telltale sign is a cystic swelling of the penile urethra. In this paper, we present two cases of CAUD that were managed by excision of the diverticulum with primary repair. PMID:26328174

  14. Emerging Drugs for Duchenne Muscular Dystrophy

    PubMed Central

    Malik, Vinod; Rodino-Klapac, Louise; Mendell, Jerry R.

    2012-01-01

    Introduction Duchenne muscular dystrophy (DMD) is the most common, severe childhood form of muscular dystrophy. Treatment is limited to glucocorticoids that have the benefit of prolonging ambulation by approximately 2 years and preventing scoliosis. Finding a more satisfactory treatment should focus on maintaining long-term efficacy with a minimal side effect profile. Areas covered Authors discuss different therapeutic strategies that have been used in pre-clinical and clinical settings. Expert opinion Multiple treatment approaches have emerged. Most attractive are molecular-based therapies that can express the missing dystrophin protein (exon skipping or mutation suppression) or a surrogate gene product (utrophin). Other approaches include increasing the strength of muscles (myostatin inhibitors), reducing muscle fibrosis, and decreasing oxidative stress. Additional targets include inhibiting NF-κB to reduce inflammation, or promoting skeletal muscle blood flow and muscle contractility using phosphodiesterase inhibitors or nitric oxide (NO) donors. The potential for each of these treatment strategies to enter clinical trials is a central theme of discussion. The review emphasizes that the goal of treatment should be to find a product at least as good as glucocorticoids with a lower side effect profile or with a significant glucocorticoid sparing effect. PMID:22632414

  15. Antisense Oligonucleotide Therapy for Inherited Retinal Dystrophies.

    PubMed

    Gerard, Xavier; Garanto, Alejandro; Rozet, Jean-Michel; Collin, Rob W J

    2016-01-01

    Inherited retinal dystrophies (IRDs) are an extremely heterogeneous group of genetic diseases for which currently no effective treatment strategies exist. Over the last decade, significant progress has been made utilizing gene augmentation therapy for a few genetic subtypes of IRD, although several technical challenges so far prevent a broad clinical application of this approach for other forms of IRD. Many of the mutations leading to these retinal diseases affect pre-mRNA splicing of the mutated genes . Antisense oligonucleotide (AON)-mediated splice modulation appears to be a powerful approach to correct the consequences of such mutations at the pre-mRNA level , as demonstrated by promising results in clinical trials for several inherited disorders like Duchenne muscular dystrophy, hypercholesterolemia and various types of cancer. In this mini-review, we summarize ongoing pre-clinical research on AON-based therapy for a few genetic subtypes of IRD , speculate on other potential therapeutic targets, and discuss the opportunities and challenges that lie ahead to translate splice modulation therapy for retinal disorders to the clinic.

  16. Oxidative stress and the pathogenesis of muscular dystrophies.

    PubMed

    Rando, Thomas A

    2002-11-01

    The muscular dystrophies represent a diverse group of diseases differing in underlying genetic basis, age of onset, mode of inheritance, and severity of progression, but they share certain common pathologic features. Most prominent among these features is the necrotic degeneration of muscle fibers. Although the genetic basis of many of the dystrophies has been known for over a decade and new disease genes continue to be discovered, the pathogenetic mechanisms leading to muscle cell death in the dystrophies remain a mystery. This review focuses on the oxidative stress theory, which states that the final common pathway of muscle cell death in these diseases involves oxidative damage.

  17. Birdshot chorioretinopathy in a male patient with facioscapulohumeral muscular dystrophy.

    PubMed

    Papavasileiou, Evangelia; Lobo, Ann-Marie

    2015-01-01

    We report a case of birdshot chorioretinopathy (BSCR) in a patient with facioscapulohumeral muscular dystrophy (FSHD). A 40-year-old male with history of facioscapulohumeral muscular dystrophy with significant facial diplegia and lagophthalmos presents for an evaluation of bilateral choroiditis with vasculitis and optic disc edema. Clinical examination included fundus and autofluorescence photographs, fluorescein angiography, and optical coherence tomography. To our knowledge, this patient represents the first reported case of birdshot chorioretinopathy with facioscapulohumeral muscular dystrophy. Patients with FSHD can present with ocular findings and should be screened with dilated fundus examinations for retinal vascular changes and posterior uveitis. PMID:25861398

  18. Benign muscular dystrophy: risk calculation in families with consanguinity.

    PubMed Central

    Wolff, G; Müller, C R; Grimm, T

    1989-01-01

    This report concerns two families in which the index patients are sporadic cases of a benign form of muscular dystrophy. In both families the sisters of the patients have married a close relative. The respective risks for a child of these consanguineous marriages being affected with either X linked Becker muscular dystrophy or autosomal recessive limb girdle muscular dystrophy is calculated using pedigree information, results of serum creatine kinase determinations, and also, in one family, results of DNA typing using RFLPs from the short arm of the X chromosome. PMID:2732990

  19. Successful treatment of atelectasis with Dornase alpha in a patient with congenital muscular dystrophy.

    PubMed

    Crescimanno, G; Marrone, O

    2014-01-01

    A 28-year-old neuromuscular patient chronically treated with nocturnal noninvasive ventilation developed pulmonary lobar atelectasis and daytime hypoxemia. Twenty four-hour 5L/min oxygen was begun, while mechanical cough assist aids were applied for seven days. In the following three days, treatment with nebulized Dornase alpha (rhDNase) b.i.d. was tested, without any significant improvement. On 11 and 13th days rhDNase was instilled by flexible bronchoscopy. A rapid resolution of the atelectasis was observed with relief of hypoxemia, without significant side effects. On day 16 the patient was discharged without oxygen requirements. In non-intubated neuromuscular patients with atelectasis who do not respond successfully to non-invasive treatments intrabronchial instillation of rhDNase may safely help to improve airway clearance. PMID:24095150

  20. Genetics Home Reference: T-cell immunodeficiency, congenital alopecia, and nail dystrophy

    MedlinePlus

    ... Accessibility FOIA Viewers & Players U.S. Department of Health & Human Services National Institutes of Health National Library of Medicine Lister Hill National Center for Biomedical Communications 8600 Rockville Pike, Bethesda, MD 20894, USA HONCode ...

  1. [Enzymopathic congenital hyperlactacidemia].

    PubMed

    Leroux, J P; Marsac, C; Saudubray, J M

    1976-01-01

    Congenital enzymopathic hyperlactacidemia results from a defect of utilisation of pyruvate either at the level of the pyruvate junction (pyruvate-carboxylase, pyruvate-dehydrogenase and Kreb's cycle), or at the level of the unidirectional enzymes on neo-glucogenesis and of neo-glycogenogenesis, e.g. glucose-6-phosphatase, phosphoenol-pyruvate-carboxykinase and glycogen synthetase. The enzymopathies which affect neoglucogenesis associate hyper-lactacidemia and fasting hypoglycemia and more or less marked hepatomegaly. Type I glycogenesis (von Gierke's disease) is the best known example. Enzymopathies which affect the pyruvate junction and the Krebs cycle, may be manifested in addition by: --either chronic neuropathies, e.g. Leigh's disease, recurrent ataxia, and moderate hyperalactacidemia,--or, as in congenital lactic acidoses, which have a rapid and severe prognosis with major hyperlactacidemia. Functional investigation, in particular, loading tests are of great value in orientation and justify the practice of tissue biopsy which permits the enzyme diagnosis. Recent, still unconfirmed knowledge of the pathogenesis of these diseases emphasizes the considerable importance of estimation of blood lactic acid in the investigation of metabolic acidoses of hereditary origin. PMID:184725

  2. Congenital Cytomegalovirus Infection.

    PubMed

    Bale, James F.; Miner, Lonnie; Petheram, Susan J.

    2002-05-01

    Intrauterine infection with cytomegalovirus (CMV), a betaherpesvirus, remains the most frequent congenital virus infection in many regions of the world. Although most CMV-infected newborns lack signs of CMV infection, approximately 10% have signs that can consist of low birth weight, jaundice, hepatosplenomegaly, skin rash, microcephaly, and chorioretinitis. Neonates with signs of CMV infection at birth have high rates of audiologic and neurodevelopmental sequelae. Although postnatal therapy with ganciclovir transiently reduces virus shedding and may lessen the audiologic consequences of CMV in some infected infants, additional strategies are needed to prevent congenital CMV disease and to improve the neurodevelopmental prognosis of infants infected with CMV in utero. Some cases of intrauterine infections can be prevented in susceptible women by avoiding contact with the urine or saliva of young children who may be shedding CMV. Vaccines against CMV remain in the experimental stages of development. Termination of pregnancy can be offered to women whose infants have evidence of intrauterine CMV infection and sonographic signs of central nervous system damage. Infants who survive symptomatic intrauterine infections have high rates of neurodevelopmental sequelae and require comprehensive evaluation and therapy through center and home-based early intervention programs. PMID:11931729

  3. [Genetics of congenital lipodystrophies].

    PubMed

    Buffet, A; Lombes, M; Caron, P

    2015-10-01

    Congenital lipodystrophies are heterogeneous genetic diseases, leading to the loss of adipose tissue. This loss of adipose tissue can be generalized or partial, thus defining different phenotypes. These lipodystrophies have a major metabolic impact, secondary to lipotoxicity. This lipotoxicity is responsible for insulin resistance, dyslipidemia and hepatic steatosis. The severity of the metabolic impact correlates with the severity of the loss of adipose tissue. Mutations in 15 predisposition genes are currently described; BSCL2 and AGPT2 genes are the major genes in the generalized forms. On the contrary, LMNA and PPARG gene mutations are recovered in partial lipodystrophies forms. These different genes encode for proteins involved in adipocyte physiology, altering adipocyte differentiation, triglycerides synthesis and lysis or playing a major role in the lipid droplet formation. Congenital lipodystrophies treatment is based on the management of metabolic comorbidities but recombinant leptin therapy appears to have promising results. These different points have been recently discussed during the 2015 Endocrine Society Congress, notably by S. O'Rahilly and are highlighted in this review.

  4. [Genetics of congenital deafness].

    PubMed

    Faundes, Víctor; Pardo, Rosa Andrea; Castillo Taucher, Silvia

    2012-10-20

    Congenital deafness is defined as the hearing loss which is present at birth and, consequently, before speech development. It is the most prevalent sensor neural disorder in developed countries, and its incidence is estimated between 1-3 children per 1,000 newborns, of which more than 50% are attributable to genetics causes. Deafness can be classified as syndromic or non-syndromic. In the first case, it is associated with outer ear malformations and/or systemic findings. More than 400 syndromes accompanied of deafness have been described, which represent about 30% of cases of congenital hearing loss. The remaining percentage corresponds to non-syndromic cases: 75-85% are autosomal recessive, 15-24% are autosomal dominant, and 1-2% are X-linked. The evaluation of a child with deafness requires a multidisciplinary collaboration among specialists, who must coordinate themselves and give information to the affected family. The aims of establishing a diagnosis are to predict other manifestations that may suggest some syndrome and to anticipate their management, as well as to perform genetic counseling to parents and affected individuals.

  5. Human muscle proteins: analysis by two-dimensional electrophoresis

    SciTech Connect

    Giometti, C.S.; Danon, M.J.; Anderson, N.G.

    1983-09-01

    Proteins from single frozen sections of human muscle were separated by two-dimensional gel electrophoresis and detected by fluorography or Coomassie Blue staining. The major proteins were identical in different normal muscles obtained from either sex at different ages, and in Duchenne and myotonic dystrophy samples. Congenital myopathy denervation atrophy, polymyositis, and Becker's muscular dystrophy samples, however, showed abnormal myosin light chain compositions, some with a decrease of fast-fiber myosin light chains and others with a decrease of slow-fiber light chains. These protein alterations did not correlate with any specific disease, and may be cause by generalized muscle-fiber damage.

  6. Acetazolamide for cystoid macular oedema in Bietti crystalline retinal dystrophy.

    PubMed

    Broadhead, Geoffrey K; Chang, Andrew A

    2014-04-01

    Bietti crystalline retinal dystrophy is a rare, inherited disorder whose hallmark is the presence of retinal crystal deposits associated with later chorioretinal degeneration. This condition may rarely be complicated by the development of cystoid macular oedema leading to rapid visual decline. Currently, treatment options for this complication of Bietti dystrophy are limited and the visual prognosis is poor. Here, we present a case of cystoid macular oedema associated with Bietti dystrophy that was successfully diagnosed using multimodal imaging techniques including optical coherence tomography and fluorescein angiography. These modalities confirmed the diagnosis of macular oedema and excluded other possible causes of oedema such as choroidal neovascularisation. In this patient, cystoid macular oedema was resolved with oral acetazolamide therapy, a treatment that has not been previously reported in this context. Acetazolamide treatment resulted in oedema resolution and improvement in visual function, and can be considered a therapeutic option for other patients with Bietti dystrophy who develop cystoid macular oedema.

  7. Macular pattern dystrophy and homonymous hemianopia in MELAS syndrome.

    PubMed

    Kamal-Salah, Radua; Baquero-Aranda, Isabel; Grana-Pérez, María Del Mar; García-Campos, Jose Manuel

    2015-03-12

    We report an unusual association of a pattern dystrophy of the retinal pigment epithelium and homonymous hemianopia in a woman diagnosed with mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes syndrome.

  8. Genetics Home Reference: limb-girdle muscular dystrophy

    MedlinePlus

    ... most common form of limb-girdle muscular dystrophy , accounting for about 30 percent of cases. Dysferlinopathy, also ... be inherited? More about Inheriting Genetic Conditions Diagnosis & Management These resources address the diagnosis or management of ...

  9. Macular pattern dystrophy and homonymous hemianopia in MELAS syndrome.

    PubMed

    Kamal-Salah, Radua; Baquero-Aranda, Isabel; Grana-Pérez, María Del Mar; García-Campos, Jose Manuel

    2015-01-01

    We report an unusual association of a pattern dystrophy of the retinal pigment epithelium and homonymous hemianopia in a woman diagnosed with mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes syndrome. PMID:25766436

  10. Bortezomib Does Not Reduce Muscular Dystrophy in the dy2J/dy2J Mouse Model of Laminin α2 Chain-Deficient Muscular Dystrophy.

    PubMed

    Körner, Zandra; Durbeej, Madeleine

    2016-01-01

    Congenital muscular dystrophy with laminin α2 chain-deficiency, also known as MDC1A, is a severe neuromuscular disorder for which there is no cure. Patients with complete laminin α2 chain-deficiency typically have an early onset disease with a more severe muscle phenotype while patients with residual laminin α2 chain expression usually have a milder disease course. Similar genotype-phenotype correlations can be seen in the dy3K/dy3K and dy2J/dy2J mouse models of MDC1A, respectively, with dy3K/dy3K mice presenting the more severe phenotype. Recently, we demonstrated that the proteasome inhibitor bortezomib partially improves muscle morphology and increases lifespan in dy3K/dy3K mice. Here, we explore the use of bortezomib in dy2J/dy2J animals. However, bortezomib neither improved histological hallmarks of disease nor increased muscle strength and locomotive activity in dy2J/dy2J mice. Altogether our data suggest that proteasome inhibition does not mitigate muscle dysfunction caused by partial laminin α2 chain-deficiency. Still, it is possible that proteasome inhibition could be useful as a supportive therapy in patients with complete absence of laminin α2 chain.

  11. MORM syndrome (mental retardation, truncal obesity, retinal dystrophy and micropenis), a new autosomal recessive disorder, links to 9q34.

    PubMed

    Hampshire, Daniel J; Ayub, Mohammed; Springell, Kelly; Roberts, Emma; Jafri, Hussain; Rashid, Yasmin; Bond, Jacquelyn; Riley, John H; Woods, C Geoffrey

    2006-05-01

    A consanguineous pedigree is described where 14 individuals are affected with a novel autosomal recessive disorder, which causes static moderate mental retardation, truncal obesity, a congenital nonprogressive retinal dystrophy and micropenis in males. We have tentatively named this condition MORM syndrome. It shows similarities to Bardet-Biedl syndrome and Cohen syndrome, but can be distinguished by clinical features; the age of onset and nonprogressive nature of the visual impairment, the lack of characteristic facies, skin or gingival infection, microcephaly, 'mottled retina', polydactyly and small penis without testicular anomalies. Furthermore, linkage to the known Bardet-Biedl (BBS1-8) and Cohen syndrome loci was excluded. Autozygosity mapping identified a single homozygous subtelomeric region shared by all affecteds on chromosome 9q34.3, with a maximum LOD score of 5.64. We believe this to be the first example of the identification of a subtelomeric recessive locus by autozygosity mapping.

  12. Dystromirs as serum biomarkers for monitoring the disease severity in Duchenne muscular Dystrophy.

    PubMed

    Zaharieva, Irina T; Calissano, Mattia; Scoto, Mariacristina; Preston, Mark; Cirak, Sebahattin; Feng, Lucy; Collins, James; Kole, Ryszard; Guglieri, Michela; Straub, Volker; Bushby, Kate; Ferlini, Alessandra; Morgan, Jennifer E; Muntoni, Francesco

    2013-01-01

    Duchenne muscular Dystrophy (DMD) is an inherited disease caused by mutations in the dystrophin gene that disrupt the open reading frame, while in frame mutations result in Becker muscular dystrophy (BMD). Ullrich congenital muscular dystrophy (UCMD) is due to mutations affecting collagen VI genes. Specific muscle miRNAs (dystromirs) are potential non-invasive biomarkers for monitoring the outcome of therapeutic interventions and disease progression. We quantified miR-1, miR-133a,b, miR-206 and miR-31 in serum from patients with DMD, BMD, UCMD and healthy controls. MiR-1, miR-133a,b and miR-206 were upregulated in DMD, but unchanged in UCMD compared to controls. Milder DMD patients had higher levels of dystromirs than more severely affected patients. Patients with low forced vital capacity (FVC) values, indicating respiratory muscle weakness, had low levels of serum miR-1 and miR-133b. There was no significant difference in the level of the dystromirs in BMD compared to controls. We also assessed the effect of dystrophin restoration on the expression of the five dystromirs in serum of DMD patients treated systemically for 12 weeks with antisense oligomer eteplirsen that induces skipping of exon 51 in the dystrophin gene. The dystromirs were also analysed in muscle biopsies of DMD patients included in a single dose intramuscular eteplirsen clinical trial. Our analysis detected a trend towards normalization of these miRNA between the pre- and post-treatment samples of the systemic trial, which however failed to reach statistical significance. This could possibly be due to the small number of patients and the short duration of these clinical trials. Although longer term studies are needed to clarify the relationship between dystrophin restoration following therapeutic intervention and the level of circulating miRNAs, our results indicate that miR-1 and miR-133 can be considered as exploratory biomarkers for monitoring the progression of muscle weakness and indirectly

  13. Muscular dystrophy of mink: a new animal model.

    PubMed

    Hegreberg, G A; Hamilton, M J; Padgett, G A

    1976-04-01

    Muscular dystrophies comprise an important group of inherited disorders of man. Although the disease has been studied extensively, little is known about the underlying primary pathomechanisms. Consequently, treatment of patients is difficult and prognosis is poor. An animal model of muscular dystrophy is a useful research tool for approaching the basic problems of pathogenesis in muscle diseases. An inherited progressive muscular dystrophy of mink which resembles the amyotonic forms of human muscular dystrophy is currently under study. Clinically, the earliest sign is progressive muscular weakness and atrophy. Muscle enzyme activities in serum are usually elevated to pathologic levels. Urinary creatine/creatinine ratio is elevated. Pathologic changes are limited to skeletal muscle and are typical of those seen in amyotonic forms of human muscular dystrophy. These changes include variation in diameter size of muscle fibers, centralized nuclei, floccular and hyaline degeneration of scattered muscle fibers, increase in connective tissue in endomysial and perimysial areas, and regenerative attempts. Both type I and type II muscle fibers are involved in the disease process. Genetic studies indicate an autosomal recessive mode of inheritance. Although the primary defect in muscular dystrophy is traditionally thought to reside in skeletal muscle, recent studies have produced theories of primary involvement of other tissues and organ systems. These theories are presented and relationships to the traditional theory are discussed.

  14. Congenital Self-Healing Reticulohistiocytosis

    PubMed Central

    Lee, Young H.; Talekar, Mala K.; Chung, Catherine G.; Bell, Moshe D.

    2014-01-01

    Congenital self-healing reticulohistiocytosis, also known as congenital self-healing Langerhans cell histiocytosis or Hashimoto-Pritzker disease, is a Langerhans cell histiocytosis. It is characterized by skin lesions in the newborn period in an otherwise healthy infant that show a Langerhans cell infiltrate in the skin on histological analysis. These findings subsequently spontaneously involute. This report describes two newborns who presented at birth with differing presentations of congenital self-healing reticulohistiocytosis. A review of the disorder, including diagnosis and evaluation, is presented. PMID:24578781

  15. Linker molecules between laminins and dystroglycan ameliorate laminin-α2–deficient muscular dystrophy at all disease stages

    PubMed Central

    Meinen, Sarina; Barzaghi, Patrizia; Lin, Shuo; Lochmüller, Hanns; Ruegg, Markus A.

    2007-01-01

    Mutations in laminin-α2 cause a severe congenital muscular dystrophy, called MDC1A. The two main receptors that interact with laminin-α2 are dystroglycan and α7β1 integrin. We have previously shown in mouse models for MDC1A that muscle-specific overexpression of a miniaturized form of agrin (mini-agrin), which binds to dystroglycan but not to α7β1 integrin, substantially ameliorates the disease (Moll, J., P. Barzaghi, S. Lin, G. Bezakova, H. Lochmuller, E. Engvall, U. Muller, and M.A. Ruegg. 2001. Nature. 413:302–307; Bentzinger, C.F., P. Barzaghi, S. Lin, and M.A. Ruegg. 2005. Matrix Biol. 24:326–332.). Now we show that late-onset expression of mini-agrin still prolongs life span and improves overall health, although not to the same extent as early expression. Furthermore, a chimeric protein containing the dystroglycan-binding domain of perlecan has the same activities as mini-agrin in ameliorating the disease. Finally, expression of full-length agrin also slows down the disease. These experiments are conceptual proof that linking the basement membrane to dystroglycan by specifically designed molecules or by endogenous ligands, could be a means to counteract MDC1A at a progressed stage of the disease, and thus opens new possibilities for the development of treatment options for this muscular dystrophy. PMID:17389231

  16. Congenital sensorineural hearing loss

    SciTech Connect

    Mafee, M.F.; Selis, J.E.; Yannias, D.A.; Valvassori, G.E.; Pruzansky, S.; Applebaum, E.L.; Capek, V.

    1984-02-01

    The ears of 47 selected patients with congenital sensorineural hearing loss were examined with complex-motion tomography. The patients were divided into 3 general categories: those with a recognized syndrome, those with sensorineural hearing loss unrelated to any known syndrome, and those with microtia. A great variety of inner ear anomalies was detected, but rarely were these characteristic of a particular clinical entity. The most common finding was the Mondini malformation or one of its variants. Isolated dysplasia of the internal auditory canal or the vestibular aqueduct may be responsible for sensorineural hearing loss in some patients. Patients with microtia may also have severe inner ear abnormalities despite the fact that the outer and inner ears develop embryologically from completely separate systems.

  17. Congenital mirror movements.

    PubMed Central

    Schott, G D; Wyke, M A

    1981-01-01

    In this report are described seven patients assessed clinically and neuropsychologically in whom mirror movements affecting predominantly the hands occurred as a congenital disorder. These mirror movements, representing a specific type of abnormal synkinesia, may arise as a hereditary condition, in the presence of a recognisable underlying neurological abnormality, and sporadically, and the seven patients provide more or less satisfactory examples of each of these three groups. Despite the apparent uniformity of the disorder, the heterogeneity and variability may be marked, examples in some of our patients including the pronounced increase in tone that developed with arm movement, and the capacity for modulation of the associated movement by alteration of neck position and bio-feedback. Various possible mechanisms are considered; these include impaired cerebral inhibition of unwanted movements, and functioning of abnormal motor pathways. Emphasis has been placed on the putative role of the direct, crossed corticomotoneurone pathways and on the unilateral and bilateral cerebral events that precede movement. PMID:7288446

  18. Congenital erythropoietic porphyria.

    PubMed

    Fritsch, C; Lang, K; Bolsen, K; Lehmann, P; Ruzicka, T

    1998-01-01

    Congenital erythropoietic porphyria (CEP) is one of the rarest autosomal-recessive disorders of the porphyrin metabolism caused by the homozygous defect of uroporphyrinogen III cosynthase. High amounts of uroporphyrin I accumulate in all cells and tissues, reflected by an increased erythrocyte porphyrin concentration and excretion of high porphyrin amounts in urine and feces. Dermal deposits of uroporphyrin frequently induce a dramatic phototoxic oxygen-dependent skin damage with extensive ulcerations and mutilations. Splenomegaly and hemolytic anemia are typical internal symptoms. Skeletal changes such as osteolysis and calcifications are frequent. Up to date 130 cases of CEP have been published. Splenectomy and erythrocyte transfusions showed some beneficial effect. Bone marrow transplantation was performed in 3 patients and stem cell transplantation in 1. The best therapy is the avoidance of sunlight. We give a report on our latest cases of CEP. PMID:10343205

  19. Oculopharyngeal muscular dystrophy: a polyalanine myopathy.

    PubMed

    Brais, Bernard

    2009-01-01

    It has been 10 years since the identification of the first PABPN1 gene (GCN)(n)/polyalanine mutations responsible for oculopharyngeal muscular dystrophy (OPMD). These mutations have been found in most cases of OPMD diagnosed in more than 35 countries. Sequence analyses have shown that such mutations have occurred numerous times in human history. Although PABPN1 was found early on to be a component of the classic filamentous intranuclear inclusions (INIs), mRNA and other proteins also have been found to coaggregate in the INIs. It is still unclear if the INIs play a pathologic or a protective role. The generation of numerous cell and animal models of OPMD has led to greater insight into its complex molecular pathophysiology and identified the first candidate therapeutic molecules. This paper reviews basic and clinical research on OPMD, with special emphasis on recent developments in the understanding of its pathophysiology.

  20. Neuromuscular function in limb girdle dystrophy.

    PubMed Central

    Belanger, A Y; McComas, A J

    1985-01-01

    The contractile properties of ankle dorsiflexor and plantarflexor muscles in 20 patients with limb girdle muscular dystrophy have been compared with those in matched controls. Twitch and voluntary torques were significantly smaller in the patient population and in nine patients it was impossible to record a twitch from tibialis anterior, a dorsiflexor muscle studied in detail. The disease process evidently ran a more rapid course in tibialis anterior than in plantarflexor muscles and this susceptibility was related to some aspect of the muscle other than its fibre type composition. Surviving fibres in dorsiflexor and plantarflexor muscles did not reveal evidence of excitation-contraction uncoupling; they exhibited normal post-activation potentiation and fatigue properties. Some patients were initially incapable of exciting their motor units maximally during voluntary contractions. A finding of possible pathogenetic significance was that one patient, with prominent calves, developed exceptionally large voluntary torque in his plantarflexor muscles. PMID:4087001

  1. Porcine Models of Muscular Dystrophy1

    PubMed Central

    Selsby, Joshua T.; Ross, Jason W.; Nonneman, Dan; Hollinger, Katrin

    2015-01-01

    Duchenne muscular dystrophy is a progressive, fatal, X-linked disease caused by a failure to accumulate the cytoskeletal protein dystrophin. This disease has been studied using a variety of animal models including fish, mice, rats, and dogs. While these models have contributed substantially to our mechanistic understanding of the disease and disease progression, limitations inherent to each model have slowed the clinical advancement of therapies, which necessitates the development of novel large-animal models. Several porcine dystrophin-deficient models have been identified, although disease severity may be so severe as to limit their potential contributions to the field. We have recently identified and completed the initial characterization of a natural porcine model of dystrophin insufficiency. Muscles from these animals display characteristic focal necrosis concomitant with decreased abundance and localization of dystrophin-glycoprotein complex components. These pigs recapitulate many of the cardinal features of muscular dystrophy, have elevated serum creatine kinase activity, and preliminarily appear to display altered locomotion. They also suffer from sudden death preceded by EKG abnormalities. Pig dystrophinopathy models could allow refinement of dosing strategies in human-sized animals in preparation for clinical trials. From an animal handling perspective, these pigs can generally be treated normally, with the understanding that acute stress can lead to sudden death. In summary, the ability to create genetically modified pig models and the serendipitous discovery of genetic disease in the swine industry has resulted in the emergence of new animal tools to facilitate the critical objective of improving the quality and length of life for boys afflicted with such a devastating disease. PMID:25991703

  2. Experimental Treatment for Duchenne Muscular Dystrophy Gets Boost from Existing Medication

    MedlinePlus

    ... 2013 March 2013 (historical) Experimental Treatment for Duchenne Muscular Dystrophy Gets Boost from Existing Medication A readily available ... effects of a promising experimental treatment for Duchenne muscular dystrophy (DMD), according to research partially funded by the ...

  3. Autosomal-Dominant Corneal Endothelial Dystrophies CHED1 and PPCD1 Are Allelic Disorders Caused by Non-coding Mutations in the Promoter of OVOL2

    PubMed Central

    Davidson, Alice E.; Liskova, Petra; Evans, Cerys J.; Dudakova, Lubica; Nosková, Lenka; Pontikos, Nikolas; Hartmannová, Hana; Hodaňová, Kateřina; Stránecký, Viktor; Kozmík, Zbyněk; Levis, Hannah J.; Idigo, Nwamaka; Sasai, Noriaki; Maher, Geoffrey J.; Bellingham, James; Veli, Neyme; Ebenezer, Neil D.; Cheetham, Michael E.; Daniels, Julie T.; Thaung, Caroline M.H.; Jirsova, Katerina; Plagnol, Vincent; Filipec, Martin; Kmoch, Stanislav; Tuft, Stephen J.; Hardcastle, Alison J.

    2016-01-01

    Congenital hereditary endothelial dystrophy 1 (CHED1) and posterior polymorphous corneal dystrophy 1 (PPCD1) are autosomal-dominant corneal endothelial dystrophies that have been genetically mapped to overlapping loci on the short arm of chromosome 20. We combined genetic and genomic approaches to identify the cause of disease in extensive pedigrees comprising over 100 affected individuals. After exclusion of pathogenic coding, splice-site, and copy-number variations, a parallel approach using targeted and whole-genome sequencing facilitated the identification of pathogenic variants in a conserved region of the OVOL2 proximal promoter sequence in the index families (c.−339_361dup for CHED1 and c.−370T>C for PPCD1). Direct sequencing of the OVOL2 promoter in other unrelated affected individuals identified two additional mutations within the conserved proximal promoter sequence (c.−274T>G and c.−307T>C). OVOL2 encodes ovo-like zinc finger 2, a C2H2 zinc-finger transcription factor that regulates mesenchymal-to-epithelial transition and acts as a direct transcriptional repressor of the established PPCD-associated gene ZEB1. Interestingly, we did not detect OVOL2 expression in the normal corneal endothelium. Our in vitro data demonstrate that all four mutated OVOL2 promoters exhibited more transcriptional activity than the corresponding wild-type promoter, and we postulate that the mutations identified create cryptic cis-acting regulatory sequence binding sites that drive aberrant OVOL2 expression during endothelial cell development. Our data establish CHED1 and PPCD1 as allelic conditions and show that CHED1 represents the extreme of what can be considered a disease spectrum. They also implicate transcriptional dysregulation of OVOL2 as a common cause of dominantly inherited corneal endothelial dystrophies. PMID:26749309

  4. [Congenital heart diseases in women].

    PubMed

    Putotto, Carolina; Unolt, Marta; Caiaro, Angela; Marino, Dario; Massaccesi, Valerio; Marino, Bruno; Digilio, Maria Cristina

    2013-02-01

    Are there gender differences in prevalence, surgical results and long-term survival of patients with congenital heart disease? Available literature data allow us to state what follows. At birth there is a mild but significant prevalence of congenital heart disease in females. The most severe congenital heart diseases are less frequent in girls, but when they are present in females, they are linked to a higher surgical mortality rate, due perhaps to lower weight at birth and to the prevalence of extracardiac malformations and/or of associated genetic syndromes. On the other hand, in adults, surgery for congenital heart disease is at higher risk in males, and so the long-term survival rate is higher in females. Particular psychological attitudes, a higher incidence of pulmonary hypertension, as well as specific problems linked to the reproductive function characterize congenital heart disease in adult women. The knowledge and analysis of these data are essential for a correct management of congenital heart disease in neonates, children and adults.

  5. FHL1 reduces dystrophy in transgenic mice overexpressing FSHD muscular dystrophy region gene 1 (FRG1).

    PubMed

    Feeney, Sandra J; McGrath, Meagan J; Sriratana, Absorn; Gehrig, Stefan M; Lynch, Gordon S; D'Arcy, Colleen E; Price, John T; McLean, Catriona A; Tupler, Rossella; Mitchell, Christina A

    2015-01-01

    Facioscapulohumeral muscular dystrophy (FSHD) is an autosomal-dominant disease with no effective treatment. The genetic cause of FSHD is complex and the primary pathogenic insult underlying the muscle disease is unknown. Several disease candidate genes have been proposed including DUX4 and FRG1. Expression analysis studies of FSHD report the deregulation of genes which mediate myoblast differentiation and fusion. Transgenic mice overexpressing FRG1 recapitulate the FSHD muscular dystrophy phenotype. Our current study selectively examines how increased expression of FRG1 may contribute to myoblast differentiation defects. We generated stable C2C12 cell lines overexpressing FRG1, which exhibited a myoblast fusion defect upon differentiation. To determine if myoblast fusion defects contribute to the FRG1 mouse dystrophic phenotype, this strain was crossed with skeletal muscle specific FHL1-transgenic mice. We previously reported that FHL1 promotes myoblast fusion in vitro and FHL1-transgenic mice develop skeletal muscle hypertrophy. In the current study, FRG1 mice overexpressing FHL1 showed an improvement in the dystrophic phenotype, including a reduced spinal kyphosis, increased muscle mass and myofiber size, and decreased muscle fibrosis. FHL1 expression in FRG1 mice, did not alter satellite cell number or activation, but enhanced myoblast fusion. Primary myoblasts isolated from FRG1 mice showed a myoblast fusion defect that was rescued by FHL1 expression. Therefore, increased FRG1 expression may contribute to a muscular dystrophy phenotype resembling FSHD by impairing myoblast fusion, a defect that can be rescued by enhanced myoblast fusion via expression of FHL1. PMID:25695429

  6. FHL1 Reduces Dystrophy in Transgenic Mice Overexpressing FSHD Muscular Dystrophy Region Gene 1 (FRG1)

    PubMed Central

    Feeney, Sandra J.; McGrath, Meagan J.; Sriratana, Absorn; Gehrig, Stefan M.; Lynch, Gordon S.; D’Arcy, Colleen E.; Price, John T.; McLean, Catriona A.; Tupler, Rossella; Mitchell, Christina A.

    2015-01-01

    Facioscapulohumeral muscular dystrophy (FSHD) is an autosomal-dominant disease with no effective treatment. The genetic cause of FSHD is complex and the primary pathogenic insult underlying the muscle disease is unknown. Several disease candidate genes have been proposed including DUX4 and FRG1. Expression analysis studies of FSHD report the deregulation of genes which mediate myoblast differentiation and fusion. Transgenic mice overexpressing FRG1 recapitulate the FSHD muscular dystrophy phenotype. Our current study selectively examines how increased expression of FRG1 may contribute to myoblast differentiation defects. We generated stable C2C12 cell lines overexpressing FRG1, which exhibited a myoblast fusion defect upon differentiation. To determine if myoblast fusion defects contribute to the FRG1 mouse dystrophic phenotype, this strain was crossed with skeletal muscle specific FHL1-transgenic mice. We previously reported that FHL1 promotes myoblast fusion in vitro and FHL1-transgenic mice develop skeletal muscle hypertrophy. In the current study, FRG1 mice overexpressing FHL1 showed an improvement in the dystrophic phenotype, including a reduced spinal kyphosis, increased muscle mass and myofiber size, and decreased muscle fibrosis. FHL1 expression in FRG1 mice, did not alter satellite cell number or activation, but enhanced myoblast fusion. Primary myoblasts isolated from FRG1 mice showed a myoblast fusion defect that was rescued by FHL1 expression. Therefore, increased FRG1 expression may contribute to a muscular dystrophy phenotype resembling FSHD by impairing myoblast fusion, a defect that can be rescued by enhanced myoblast fusion via expression of FHL1. PMID:25695429

  7. [Congenital lumbar hernia].

    PubMed

    Peláez Mata, D J; Alvarez Muñoz, V; Fernández Jiménez, I; García Crespo, J M; Teixidor de Otto, J L

    1998-07-01

    Hernias in the lumbar region are abdominal wall defects that appear in two possible locations: the superior lumbar triangle of Grynfelt-Lesshaft and the inferior lumbar triangle of Petit. There are 40 cases reported in the pediatric literature, and only 16 are considered congenital, associated with the lumbocostovertebral syndrome and/or meningomyelocele. A new case is presented. A premature newborn with a mass in the left flank that increases when the patient cries and reduces easily. The complementary studies confirm the diagnosis of lumbar hernia and reveal the presence of lumbocostovertebral syndrome associated. At the time of operation a well defined fascial defect at the superior lumbar triangle of Grynfelt-Lesshaft is primarily closed. The diagnosis of lumbar hernia is not difficult to establish but it is necessary the screening of the lumbocostovertebral syndrome. We recommend the surgical treatment before 12 months of age; the objective is to close the defect primarily or to use prosthetic material if necessary. PMID:12602034

  8. [Consanguinity and congenital abnormalities].

    PubMed

    Søgaard, Marie; Vedsted-Jakobsen, Agnete

    2003-04-28

    Knowledge of consanguinity is relevant for employees in the Danish national health service, since about 7.5% of the Danish population has another ethnic background than Danish and the majority comes from cultures where consanguineous marriages are not unusual. In the literature it is found that consanguineous couples have a higher risk of having children with congenital malformations. The risk is increased by a factor 2 to 2 1/2. The average risk in Denmark is about 3%. Primarily, the autosomal recessive diseases are expressed in children with consanguineous parents. In order to advise and diagnose it is essential to clarify the consanguinity state. In case of pregnancy with consanguineous parents, we recommend: 1) Counselling to estimate the risk of foetal illness and information about possible examination possibilities. 2) An ultrasound scan at the gestational age of 11-14 weeks in order to measure nuchal translucency and an early malformation scan. 3) An ultrasound scan for malformations at the gestational age of 18-20 weeks. 4) An ultrasound scan especially in order to detect foetal heart malformations at the gestational age of 20-24 weeks.

  9. Congenital mirror movements

    PubMed Central

    Méneret, Aurélie; Depienne, Christel; Riant, Florence; Trouillard, Oriane; Bouteiller, Delphine; Cincotta, Massimo; Bitoun, Pierre; Wickert, Julia; Lagroua, Isabelle; Westenberger, Ana; Borgheresi, Alessandra; Doummar, Diane; Romano, Marcello; Rossi, Simone; Defebvre, Luc; De Meirleir, Linda; Espay, Alberto J.; Fiori, Simona; Klebe, Stephan; Quélin, Chloé; Rudnik-Schöneborn, Sabine; Plessis, Ghislaine; Dale, Russell C.; Sklower Brooks, Susan; Dziezyc, Karolina; Pollak, Pierre; Golmard, Jean-Louis; Vidailhet, Marie; Brice, Alexis

    2014-01-01

    Objective: We screened a large series of individuals with congenital mirror movements (CMM) for mutations in the 2 identified causative genes, DCC and RAD51. Methods: We studied 6 familial and 20 simplex CMM cases. Each patient had a standardized neurologic assessment. Analysis of DCC and RAD51 coding regions included Sanger sequencing and a quantitative method allowing detection of micro rearrangements. We then compared the frequency of rare variants predicted to be pathogenic by either the PolyPhen-2 or the SIFT algorithm in our population and in the 4,300 controls of European origin on the Exome Variant Server. Results: We found 3 novel truncating mutations of DCC that segregate with CMM in 4 of the 6 families. Among the 20 simplex cases, we found one exonic deletion of DCC, one DCC mutation leading to a frameshift, 5 missense variants in DCC, and 2 missense variants in RAD51. All 7 missense variants were predicted to be pathogenic by one or both algorithms. Statistical analysis showed that the frequency of variants predicted to be deleterious was significantly different between patients and controls (p < 0.001 for both RAD51 and DCC). Conclusion: Mutations and variants in DCC and RAD51 are strongly associated with CMM, but additional genes causing CMM remain to be discovered. PMID:24808016

  10. [Congenital foot abnormalities].

    PubMed

    Delpont, M; Lafosse, T; Bachy, M; Mary, P; Alves, A; Vialle, R

    2015-03-01

    The foot may be the site of birth defects. These abnormalities are sometimes suspected prenatally. Final diagnosis depends on clinical examination at birth. These deformations can be simple malpositions: metatarsus adductus, talipes calcaneovalgus and pes supinatus. The prognosis is excellent spontaneously or with a simple orthopedic treatment. Surgery remains outstanding. The use of a pediatric orthopedist will be considered if malposition does not relax after several weeks. Malformations (clubfoot, vertical talus and skew foot) require specialized care early. Clubfoot is characterized by an equine and varus hindfoot, an adducted and supine forefoot, not reducible. Vertical talus combines equine hindfoot and dorsiflexion of the forefoot, which is performed in the midfoot instead of the ankle. Skew foot is suspected when a metatarsus adductus is resistant to conservative treatment. Early treatment is primarily orthopedic at birth. Surgical treatment begins to be considered after walking age. Keep in mind that an abnormality of the foot may be associated with other conditions: malposition with congenital hip, malformations with syndromes, neurological and genetic abnormalities. PMID:25524290

  11. Modifier Genes and their effect on Duchenne Muscular Dystrophy

    PubMed Central

    Vo, Andy H.; McNally, Elizabeth M.

    2015-01-01

    Purpose of Review Recently, genetic pathways that modify the clinical severity of Duchenne Muscular Dystrophy have been identified. The pathways uncovered as modifiers are useful to predict prognosis and also elucidate molecular signatures that can be manipulated therapeutically. Recent Findings Modifiers have been identified using combinations of transcriptome and genome profiling. Osteopontin, encoded by the SPP1 gene, was found using gene expression profiling. LTBP4, encoding latent transforming growth factor β binding protein 4 was initially discovered using a genomewide screen in mice and then validated in cohorts of Duchenne Muscular Dystrophy patients. These two pathways converge in that they both regulate TGFβ. A third modifier, Anxa6 that specifies annexin A6, is a calcium binding protein has been identified using mouse models, and regulates the injury pathway and sarcolemmal resealing. Summary Genetic modifiers can serve as biomarkers for outcomes in Duchenne Muscular Dystrophy. Modifiers can alter strength and ambulation in muscular dystrophy, and these same features can be used as endpoints used in clinical trials. Moreover, because genetic modifiers can influence outcomes, these genetic markers should be considered when stratifying results in muscular dystrophy. PMID:26263473

  12. Neurocognitive Profiles in Duchenne Muscular Dystrophy and Gene Mutation Site

    PubMed Central

    D’Angelo, Maria Grazia; Lorusso, Maria Luisa; Civati, Federica; Comi, Giacomo Pietro; Magri, Francesca; Del Bo, Roberto; Guglieri, Michela; Molteni, Massimo; Turconi, Anna Carla; Bresolin, Nereo

    2011-01-01

    The presence of nonprogressive cognitive impairment is recognized as a common feature in a substantial proportion of patients with Duchenne muscular dystrophy. To investigate the possible role of mutations along the dystrophin gene affecting different brain dystrophin isoforms and specific cognitive profiles, 42 school-age children affected with Duchenne muscular dystrophy, subdivided according to sites of mutations along the dystrophin gene, underwent a battery of tests tapping a wide range of intellectual, linguistic, and neuropsychologic functions. Full-scale intelligence quotient was approximately 1 S.D. below the population average in the whole group of dystrophic children. Patients with Duchenne muscular dystrophy and mutations located in the distal portion of the dystrophin gene (involving the 140-kDa brain protein isoform, called Dp140) were generally more severely affected and expressed different patterns of strengths and impairments, compared with patients with Duchenne muscular dystrophy and mutations located in the proximal portion of the dystrophin gene (not involving Dp140). Patients with Duchenne muscular dystrophy and distal mutations demonstrated specific impairments in visuospatial functions and visual memory (which seemed intact in proximally mutated patients) and greater impairment in syntactic processing. PMID:22000308

  13. Next generation sequencing based identification of disease-associated mutations in Swiss patients with retinal dystrophies

    PubMed Central

    Tiwari, Amit; Bahr, Angela; Bähr, Luzy; Fleischhauer, Johannes; Zinkernagel, Martin S.; Winkler, Niklas; Barthelmes, Daniel; Berger, Lieselotte; Gerth-Kahlert, Christina; Neidhardt, John; Berger, Wolfgang

    2016-01-01

    Inherited monogenic diseases of the retina and vitreous affect approximately 1 in 2000 individuals. They are characterized by tremendous genetic heterogeneity and clinical variability involving mutations in approximately 250 genes and more than 20 different clinical phenotypes. Clinical manifestations of retinal dystrophies (RDs) range from mild retinal dysfunctions to severe congenital forms of blindness. A detailed clinical diagnosis and the identification of causative mutations are crucial for genetic counseling of affected patients and their families, for understanding genotype-phenotype correlations and developing therapeutic approaches. Using whole exome sequencing (WES) we have established a reliable and efficient high-throughput analysis pipeline to identify disease-causing mutations. Our data indicate that this approach enables us to genetically diagnose approximately 64% of the patients (n = 58) with variant(s) in known disease-associated genes. We report 20 novel and 26 recurrent variants in genes associated with RDs. We also identified a novel phenotype for mutations in C2orf71 and provide functional evidence for exon skipping due to a splice-site variant identified in FLVCR1. In conclusion, WES can rapidly identify variants in various families affected with different forms of RDs. Our study also expands the clinical and allelic spectrum of genes associated with RDs in the Swiss population. PMID:27353947

  14. Omigapil ameliorates the pathology of muscle dystrophy caused by laminin-alpha2 deficiency.

    PubMed

    Erb, Michael; Meinen, Sarina; Barzaghi, Patrizia; Sumanovski, Lazar T; Courdier-Früh, Isabelle; Rüegg, Markus A; Meier, Thomas

    2009-12-01

    Laminin alpha2-deficient congenital muscular dystrophy, called MDC1A, is a rare, devastating genetic disease characterized by severe neonatal hypotonia ("floppy infant syndrome"), peripheral neuropathy, inability to stand or walk, respiratory distress, and premature death in early life. Transgenic overexpression of the apoptosis inhibitor protein BCL-2, or deletion of the proapoptotic Bax gene in a mouse model for MDC1A prolongs survival and mitigates pathology, indicating that apoptotic events are involved in the pathology. Here we demonstrate that the proapoptotic glyceraldehyde-3-phosphate dehydrogenase (GAPDH)-Siah1-CBP/p300-p53 pathway is activated in a mouse model for MDC1A. Moreover, we show that omigapil, which inhibits GAPDH-Siah1-mediated apoptosis, ameliorates several pathological hallmarks in the MDC1A mouse model. Specifically, we demonstrate that treatment with omigapil inhibits apoptosis in muscle, reduces body weight loss and skeletal deformation, increases locomotive activity, and protects from early mortality. These data qualify omigapil, which is in late phase of clinical development for human use, as a drug candidate for the treatment of MDC1A.

  15. [Specific features of Becker Muscular Dystrophy patients and female carriers of Duchenne Muscular Dystrophy].

    PubMed

    Magot, A; Mercier, S; Péréon, Y

    2015-12-01

    Becker muscular dystrophy (BMD) was first described in 1955 and linked to the DMD gene in 1987. Compared to Duchenne muscular dystrophy (DMD), clinical onset of BMD usually occurs after the age of 12 and wheelchair is required after the age of 16. BMD is characterized by generalized weakness first affecting limb girdle muscles, hypertrophy of the calves and cardiomyopathy in males. Some patients have only mild symptoms such as cramps or elevated serum creatine kinases (SCK) throughout all their lives. SCK levels are usually elevated. Muscle biopsy (immunohistochemistry or immunoblotting) shows a dystrophic pattern with abnormal dystrophin staining. Diagnosis is confirmed by DMD gene sequencing. Deletions or duplications of one or several exons are identified in the majority of cases. A multidisciplinary approach is recommended for the care management of these patients with a particular attention to the cardiomyopathy, which is typically responsible for death but can be prevented by specific treatment. X-linked dilated cardiomyopathies linked to DMD gene are a phenotypic continuum of BMD. Some female carriers of DMD mutations exhibit clinical symptoms of variable severity, often milder and beginning later than in males. The cardiomyopathy is the most frequent feature that should be especially monitored in these patients. Genetic counselling should be systematically proposed. PMID:26773584

  16. Congenital Scoliosis (Mini-review).

    PubMed

    Weiss, Hans-Rudolf; Moramarco, Marc

    2016-01-01

    Congenital scoliosis is a lateral deformity of the spine with a disturbance of the sagittal profile caused by malformations of vertebra and ribs. Typically, early surgical intervention is the suggested treatment (before three-years-old) for young patients with congenital scoliosis. While a previous study was conducted in 2011 to investigate long-term studies supporting the necessity for this recommendation and no evidence was found, this current review, is an updated search for evidence published from 2011 through March 2015. This also failed to find any prospective or randomized controlled studies to support the hypothesis that spinal fusion surgery in patients with congenital scoliosis should be considered as evidence-based treatment. Contradictory results exist on the safety of hemivertebra resection and segmental fusion using pedicle screw fixation. When using the VEPTR (vertical expandable prosthetic titanium rib) device, studies show a high rate of complications exist. It is difficult to predict the final outcome for patients with congenital scoliosis. However, it is possible that many patients with congenital scoliosis may be able to avoid spinal surgery with the application of advanced bracing technology. Therefore, it is only prudent to advocate for conservative management first before spinal surgery is considered. PMID:26769614

  17. Congenital Scoliosis (Mini-review).

    PubMed

    Weiss, Hans-Rudolf; Moramarco, Marc

    2016-01-01

    Congenital scoliosis is a lateral deformity of the spine with a disturbance of the sagittal profile caused by malformations of vertebra and ribs. Typically, early surgical intervention is the suggested treatment (before three-years-old) for young patients with congenital scoliosis. While a previous study was conducted in 2011 to investigate long-term studies supporting the necessity for this recommendation and no evidence was found, this current review, is an updated search for evidence published from 2011 through March 2015. This also failed to find any prospective or randomized controlled studies to support the hypothesis that spinal fusion surgery in patients with congenital scoliosis should be considered as evidence-based treatment. Contradictory results exist on the safety of hemivertebra resection and segmental fusion using pedicle screw fixation. When using the VEPTR (vertical expandable prosthetic titanium rib) device, studies show a high rate of complications exist. It is difficult to predict the final outcome for patients with congenital scoliosis. However, it is possible that many patients with congenital scoliosis may be able to avoid spinal surgery with the application of advanced bracing technology. Therefore, it is only prudent to advocate for conservative management first before spinal surgery is considered.

  18. De novo facioscapulohumeral muscular dystrophy defined by DNA probe p13E-11 (D4F104S1).

    PubMed Central

    Jardine, P E; Koch, M C; Lunt, P W; Maynard, J; Bathke, K D; Harper, P S; Upadhyaya, M

    1994-01-01

    Facioscapulohumeral muscular dystrophy (FSHD) is an autosomal dominant condition with variable age of onset and severity. Identification of a de novo DNA fragment by probe p13E-11 (D4F104S1) established the diagnosis of new mutation FSHD in 27 of 31 sporadic cases. The clinical data for these certain new mutation cases were as follows: 13 boys, 14 girls; mean age of onset 6.8 years; significant leg weakness in 19/27 (70%) (8/27 (30%) used wheelchairs at a mean age of 17.7 years); high tone sensorineural deafness in 10/27; visual acuity and direct ophthalmoscopy were normal. Congenital facial diplegia and sensorineural deafness in three children suggest that infantile FSHD is not a genetically separate disorder from FSHD. Ascertainment bias may explain the difference in severity between this group and typical familial cases. Molecular analysis for FSHD should be considered in children with either congenital or early onset facial weakness or diplegia. Images PMID:7979495

  19. Targeting Fibrosis in Duchenne Muscular Dystrophy

    PubMed Central

    Zhou, Lan; Lu, Haiyan

    2010-01-01

    Duchenne muscular dystrophy (DMD) is the most common genetic muscle disease affecting 1 in 3,500 live male births. It is an X-linked recessive disease caused by a defective dystrophin gene. The disease is characterized by progressive limb weakness, respiratory and cardiac failure and premature death. Fibrosis is a prominent pathological feature of muscle biopsies from patients with DMD. It directly causes muscle dysfunction and contributes to the lethal DMD phenotype. Although gene therapy and cell therapy may ultimately provide a cure for DMD, currently the disease is devastating, with no effective therapies. Recent studies have demonstrated that ameliorating muscle fibrosis may represent a viable therapeutic approach for DMD. By reducing scar formation, antifibrotic therapies may not only improve muscle function but also enhance muscle regeneration and promote gene and stem cell engraftment. Antifibrotic therapy may serve as a necessary addition to gene and cell therapies to treat DMD in the future. Therefore, understanding cellular and molecular mechanisms underlying muscle fibrogenesis associated with dystrophin deficiency is key to the development of effective antifibrotic therapies for DMD. PMID:20613637

  20. Facioscapulohumeral muscular dystrophy: consequences of chromatin relaxation

    PubMed Central

    van der Maarel, Silvère M.; Miller, Daniel G.; Tawil, Rabi; Filippova, Galina N.; Tapscott, Stephen J.

    2013-01-01

    Purpose of review In recent years we have seen remarkable progress in our understanding of the disease mechanism underlying facioscapulohumeral muscular dystrophy (FSHD). The purpose of this review is to provide a comprehensive overview of our current understanding of the disease mechanism and to discuss the observations supporting the possibility of a developmental defect in this disorder. Recent findings In the majority of cases FSHD is caused by contraction of the D4Z4 repeat array (FSHD1). This results in local chromatin relaxation and stable expression of the DUX4 retrogene in skeletal muscle, but only when a polymorphic DUX4 polyadenylation signal is present. In some cases (FSHD2), D4Z4 chromatin relaxation and stable DUX4 expression occurs in the absence of D4Z4 array contraction. DUX4 is a germline transcription factor and its expression in skeletal muscle leads to activation of early stem cell and germline programs and transcriptional activation of retroelements. Summary Recent studies have provided a plausible disease mechanism for FSHD where FSHD results from inappropriate expression of the germline transcription factor DUX4. The genes regulated by DUX4 suggest several mechanisms of muscle damage, and provide potential biomarkers and therapeutic targets that should be investigated in future studies. PMID:22892954

  1. Optimizing Bone Health in Duchenne Muscular Dystrophy

    PubMed Central

    Buckner, Jason L.; Bowden, Sasigarn A.; Mahan, John D.

    2015-01-01

    Duchenne muscular dystrophy (DMD) is an X-linked recessive disorder characterized by progressive muscle weakness, with eventual loss of ambulation and premature death. The approved therapy with corticosteroids improves muscle strength, prolongs ambulation, and maintains pulmonary function. However, the osteoporotic impact of chronic corticosteroid use further impairs the underlying reduced bone mass seen in DMD, leading to increased fragility fractures of long bones and vertebrae. These serious sequelae adversely affect quality of life and can impact survival. The current clinical issues relating to bone health and bone health screening methods in DMD are presented in this review. Diagnostic studies, including biochemical markers of bone turnover and bone mineral density by dual energy X-ray absorptiometry (DXA), as well as spinal imaging using densitometric lateral spinal imaging, and treatment to optimize bone health in patients with DMD are discussed. Treatment with bisphosphonates offers a method to increase bone mass in these children; oral and intravenous bisphosphonates have been used successfully although treatment is typically reserved for children with fractures and/or bone pain with low bone mass by DXA. PMID:26124831

  2. Autophagy in granular corneal dystrophy type 2.

    PubMed

    Choi, Seung-Il; Kim, Eung Kweon

    2016-03-01

    Autophagy is a lysosomal degradative process that is essential for cellular homeostasis and metabolic stress adaptation. Defective autophagy is involved in the pathogenesis of many diseases including granular corneal dystrophy type 2 (GCD2). GCD2 is an autosomal dominant disorder caused by substitution of histidine for arginine at codon 124 (R124H) in the transforming growth factor β-induced gene (TGFBI) on chromosome 5q31. Transforming growth factor β-induced protein (TGFBIp) is degraded by autophagy, but mutant-TGFBIp accumulates in autophagosomes and/or lysosomes, despite significant activation of basal autophagy, in GCD2 corneal fibroblasts. Furthermore, inhibition of autophagy induces cell death of GCD2 corneal fibroblasts through active caspase-3. As there is currently no pharmacological treatment for GCD2, development of novel therapies is required. A potential strategy for preventing cytoplasmic accumulation of mutant-TGFBIp in GCD2 corneal fibroblasts is to enhance mutant-TGFBIp degradation. This could be achieved by activation of the autophagic pathway. Here, we will consider the role and the potential therapeutic benefits of autophagy in GCD2, with focus on TGFBIp degradation, in light of the recently established role of autophagy in protein degradation.

  3. Molecular analysis of facioscapulohumeral muscular dystrophy (FSHD)

    SciTech Connect

    Upadhyaya, M.; Maynard, J.; Osborn, M.

    1994-09-01

    Facioscapulohumeral muscular dystrophy (FSHD) is an autosomal dominant disorder characterized by progressive muscle weakness. The disease locus maps to 4q35 and is associated with a de novo DNA rearrangement, detected by a probe p13E-11 (D4F104S1) which maps proximal to the disease locus. An informative distal flanking marker for this condition is still required. Using p13E-11, we have analyzed 35 FSHD families in which the disease is apparently associated with a new mutation. Twenty three of these cases were found to have a smaller rearranged DNA fragment which was not present in either of the parents. Pulsed-field gel analysis of 5 of these families also revealed evidence of DNA deletion. During the course of this study, we identified one case with a DNA rearrangement which was also present in the unaffected mother, but at very low intensity. This finding has been confirmed by pulsed-field gel analysis, and indicates that the mother is probably a gonosomal mosaic. In order to saturate the FSHD region with new DNA markers, a laser microdissection and microcloning technique was used to construct a genomic library from the distal end of chromosome 4. Of the 72 microclones analyzed, 42 mapped into the relevant 4q35 region. 4 sequences were conserved and may be considered potential candidate genes for FSHD. The microclones mapping to 4q35 are under study to identify additional polymorphic markers for the FSHD region.

  4. Measuring quality of life in muscular dystrophy

    PubMed Central

    Abresch, Richard T.; Biesecker, Barbara; Conway, Kristin Caspers; Heatwole, Chad; Peay, Holly; Scal, Peter; Strober, Jonathan; Uzark, Karen; Wolff, Jodi; Margolis, Marjorie; Blackwell, Angela; Street, Natalie; Montesanti, Angela; Bolen, Julie

    2015-01-01

    Objectives: The objectives of this study were to develop a conceptual model of quality of life (QOL) in muscular dystrophies (MDs) and review existing QOL measures for use in the MD population. Methods: Our model for QOL among individuals with MD was developed based on a modified Delphi process, literature review, and input from patients and patient advocacy organizations. Scales that have been used to measure QOL among patients with MD were identified through a literature review and evaluated using the COSMIN (Consensus-Based Standards for the Selection of Health Measurement Instruments) checklist. Results: The Comprehensive Model of QOL in MD (CMQM) captures 3 broad domains of QOL (physical, psychological, and social), includes factors influencing self-reported QOL (disease-related factors, support/resources, and expectations/aspirations), and places these concepts within the context of the life course. The literature review identified 15 QOL scales (9 adult and 6 pediatric) that have been applied to patients with MD. Very few studies reported reliability data, and none included data on responsiveness of the measures to change in disease progression, a necessary psychometric property for measures included in treatment and intervention studies. No scales captured all QOL domains identified in the CMQM model. Conclusions: Additional scale development research is needed to enhance assessment of QOL for individuals with MD. Item banking and computerized adaptive assessment would be particularly beneficial by allowing the scale to be tailored to each individual, thereby minimizing respondent burden. PMID:25663223

  5. Treatment of congenital malformations.

    PubMed

    Brucker, Sara Yvonne; Rall, Katharina; Campo, Rudi; Oppelt, Peter; Isaacson, Keith

    2011-03-01

    The prevalence of müllerian malformations is 1 in 200, or 0.5%. A third of the anomalies are septate, a third bicornuate uteri, 10% arcuate uterus, 10% didelphis and unicornuate uterus, and < 5% uterine and vaginal aplasia. Correct diagnosis of the malformation is most important but often very difficult. Correct treatment can only be performed if the malformation is clear. Longitudinal vaginal septums have to be removed due to potential obstetric problems. Transverse vaginal septums can cause hematocolpos and pain and have to be incised crosswise and excised so as not to shorten the vagina at the same time. Congenital vaginal agenesis occurs in Mayer-Rokitansky-Kuster-Hauser syndrome patients and in androgen insensitivity syndrome. The first choice for surgical treatment should be the new laparoscopic-assisted creation of a neovagina. Septate uterus has to be distinguished from a bicornuate uterus. Even if it is not proven to be a cause for infertility, the chance of miscarriage can be diminished by performing hysteroscopic metroplasty. Repair of a uterine septum in infertility patients often improves pregnancy rates. In contrast, surgical repair of a bicornuate uterus requires an abdominal metroplasty. This should only be performed if the patient has recurrent fetal loss due to the uterine structural defect. In a unicornuate uterus it is most important to determine if there is a second uterine horn that can cause cyclic pain if it has functioning endometrium. The only surgical option in these cases is to remove the rudimentary uterus with endometrium and hematometra, respectively.

  6. Cognitive and Neurobehavioral Profile in Boys With Duchenne Muscular Dystrophy.

    PubMed

    Banihani, Rudaina; Smile, Sharon; Yoon, Grace; Dupuis, Annie; Mosleh, Maureen; Snider, Andrea; McAdam, Laura

    2015-10-01

    Duchenne muscular dystrophy is a progressive neuromuscular condition that has a high rate of cognitive and learning disabilities as well as neurobehavioral disorders, some of which have been associated with disruption of dystrophin isoforms. Retrospective cohort of 59 boys investigated the cognitive and neurobehavioral profile of boys with Duchenne muscular dystrophy. Full-scale IQ of < 70 was seen in 27%; learning disability in 44%, intellectual disability in 19%; attention-deficit/hyperactivity disorder in 32%; autism spectrum disorders in 15%; and anxiety in 27%. Mutations affecting Dp260 isoform and 5'untranslated region of Dp140 were observed in 60% with learning disability, 50% intellectual disability, 77% with autism spectrum disorders, and 94% with anxiety. No statistically significant correlation was noted between comorbidities and dystrophin isoforms; however, there is a trend of cumulative loss of dystrophin isoforms with declining full-scale IQ. Enhanced psychology testing to include both cognitive and neurobehavioral disorders is recommended for all individuals with Duchenne muscular dystrophy.

  7. Genetics Home Reference: congenital dyserythropoietic anemia

    MedlinePlus

    ... Understand Genetics Home Health Conditions CDA congenital dyserythropoietic anemia Enable Javascript to view the expand/collapse boxes. ... PDF Open All Close All Description Congenital dyserythropoietic anemia ( CDA ) is an inherited blood disorder that affects ...

  8. Care and Treatment for Congenital Heart Defects

    MedlinePlus

    ... Physical Activity Recommendations for Heart Health • Tools & Resources Web Booklets on Congenital Heart Defects These online publications ... to you or your child’s defect and concerns. Web Booklet: Adults With Congenital Heart Defects Web Booklet: ...

  9. Genetic Counseling for Congenital Heart Defects

    MedlinePlus

    ... Pressure High Blood Pressure Tools & Resources Stroke More Genetic Counseling for Congenital Heart Defects Updated:Oct 26, ... person with congenital heart disease considers having children. Genetic counseling can help answer these questions and address ...

  10. Magnetic resonance imaging of congenital heart disease

    SciTech Connect

    Fletcher, B.D.; Jacobstein, M.D.

    1988-01-01

    Focusing primarily on MR imaging of the heart, this book covers other diagnostic imaging modalities as well. The authors review new technologies and diagnostic procedures pertinent to congenital heat disease and present each congenital heat abnormality as a separate entity.

  11. Congenital Anomalies of the Limbs

    PubMed Central

    Gingras, G.; Mongeau, M.; Moreault, P.; Dupuis, M.; Hebert, B.; Corriveau, C.

    1964-01-01

    As a preparatory step towards the development of a complete habilitation program for children with congenital limb anomalies associated with maternal ingestion of thalidomide, the medical records of all patients with congenital limb anomalies referred to the Rehabilitation Institute of Montreal in the past decade were studied, and an examination and a thorough reassessment were made of 41 patients (21 males and 20 females). In this paper, Part I, the medical and prosthetic aspects are dealt with and a form of management is described for each type of anomaly. The conclusions are reached that prosthetic fitting and training should be initiated very early in life and that co-operation of the parent is essential to successful habilitation of a child with congenital limb anomalies. ImagesFig. 1Fig. 2Fig. 3Fig. 4Fig. 5Fig. 6Fig. 7 PMID:14154297

  12. [DIAGNOSTIC VARIATIONS OF X-LINKED MUSCULAR DYSTROPHY WITH CONTRACTURES].

    PubMed

    Kvirkvelia, N; Shakarishvili, R; Gugutsidze, D; Khizanishvili, N

    2015-01-01

    Case report with review describes X-linked muscular dystrophy with contractures in 28 years old man and his cousin. The disease revealed itself in an early stage (age 5-10), the process was progressing with apparent tendons retraction and contraction, limited movement in the areas of the neck and back of spine, atrophy of shoulder and pelvic yard and back muscles. Intellect was intact. Cardyomyopathy was exhibited. CK was normal. EMG showed classic myopathic features. Muscle biopsy showed different caliber groups of muscle fibers, growth of endo-perimesial connective tissue. Clinical manifestations together with electrophysiological and histological data suggest consistency with Rotthauwe-Mortier-Bayer X-linked muscular dystrophy.

  13. Dystrophin and muscular dystrophy: past, present, and future.

    PubMed

    O'Brien, K F; Kunkel, L M

    2001-01-01

    Duchenne muscular dystrophy was described in the medical literature in the early 1850s but the molecular basis of the disease was not determined until the late 1980s. The cloning of dystrophin led to the identification of a large complex of proteins that plays an important, although not yet well understood, role in muscle biology. Concomitant with the elucidation of the function of dystrophin and its associated proteins has been the pursuit of therapeutic options for muscular dystrophy. Although there is still no cure for this disorder, great advances are being made in the areas of gene introduction and cell transplant therapy. PMID:11592805

  14. Immobility reduces muscle fiber necrosis in dystrophin deficient muscular dystrophy.

    PubMed

    Kimura, S; Ikezawa, M; Nomura, K; Ito, K; Ozasa, S; Ueno, H; Yoshioka, K; Yano, S; Yamashita, T; Matuskura, M; Miike, T

    2006-08-01

    Duchenne/Becker muscular dystrophy is a progressive muscle disease, which is caused by the abnormality of dystrophin. Spina bifida is characterized by paralysis of the feet, with most of the upper extremities not being affected. We report here on the first case of Becker muscular dystrophy coinciding with spina bifida. The muscle biopsy specimens of the patient showed dystrophic changes in upper extremities, but clearly less in lower extremities. The results show that the restriction of excessive exercise is important for dystrophin deficiency disease. PMID:16516424

  15. Determinants of the incidence of Duchenne muscular dystrophy

    PubMed Central

    2015-01-01

    Duchenne muscular dystrophy (DMD), an X-linked disorder, is the most common muscular dystrophy with an incidence in boys of about 200 per million births. It presents in early childhood leading to death in early teens. Its relatively high incidence and severity have stimulated many studies from epidemiological to curative. Recent advances in molecular biology have opened up the possibility of carrier identification and potential reduction of the incidence of cases. This paper gives a population genetics model which can be used to predict the reduction in incidence. PMID:26697447

  16. Dupuytren's Contracture Cosegregation with Limb-Girdle Muscle Dystrophy

    PubMed Central

    Lace, Baiba; Inashkina, Inna; Micule, Ieva; Vasiljeva, Inta; Naudina, Maruta Solvita; Jankevics, Eriks

    2013-01-01

    Limb-girdle muscular dystrophies (LGMDs) is a heterogeneous group of muscular dystrophies that mostly affect the pelvic and shoulder girdle muscle groups. We report here a case of neuromuscular disease associated with Dupuytren's contracture, which has never been described before as cosegregating with an autosomal dominant type of inheritance. Dupuytren's contracture is a common disease, especially in Northern Europe. Comorbid conditions associated with Dupuytren's contracture are repetitive trauma to the hands, diabetes, and seizures, but it has never before been associated with neuromuscular disease. We hypothesize that patients may harbor mutations in genes with functions related to neuromuscular disease and Dupuytren's contracture development. PMID:24024053

  17. Torn apart: membrane rupture in muscular dystrophies and associated cardiomyopathies

    PubMed Central

    Lammerding, Jan; Lee, Richard T.

    2007-01-01

    Muscular dystrophies are often caused by mutations in cytoskeletal proteins that render cells more susceptible to strain-induced injury in mechanically active tissues such as skeletal or cardiac muscle. In this issue of the JCI, Han et al. report that dysferlin participates in membrane resealing in cardiomyocytes and that exercise results in increased membrane damage and disturbed cardiac function in dysferlin-deficient mice (see the related article beginning on page 1805). Thus, in addition to repetitive membrane damage, inadequate membrane repair may participate in the pathogenesis of muscular dystrophies and cardiomyopathies. PMID:17607350

  18. Congenital Sialolipoma in an Infant.

    PubMed

    Mazlumoglu, Muhammed Recai; Altas, Enver; Oner, Fatih; Ucuncu, Harun; Calik, Muhammed

    2015-11-01

    Sialolipoma is a newly recognized tumor of the major and minor salivary glands and represents only 0.3% of all salivary gland tumors. Only 3 cases of congenital sialolipoma are available in the literature. In the current case, we performed a total parotidectomy with facial nerve preservation on a 12-week-old infant exhibiting huge mass in the parotid region. Histopathology results showed sialolipoma. There was no recurrence at the 18-month follow-up. Although it is a very rare disease in infants, congenital sialolipoma should be kept in mind in patients with parotid mass. The primary treatment is parotidectomy with facial nerve preservation. PMID:26594977

  19. [Congenital lumbar hernia and bilateral renal agenesis].

    PubMed

    Barrero Candau, R; Garrido Morales, M

    2007-04-01

    We report a new case of congenital lumbar hernia. This is first case reported of congenital lumbar hernia and bilateral renal agenesis. We review literature and describe associated malformations reported that would be role out in every case of congenital lumbar hernia. PMID:17650728

  20. [Congenital lumbar hernia and bilateral renal agenesis].

    PubMed

    Barrero Candau, R; Garrido Morales, M

    2007-04-01

    We report a new case of congenital lumbar hernia. This is first case reported of congenital lumbar hernia and bilateral renal agenesis. We review literature and describe associated malformations reported that would be role out in every case of congenital lumbar hernia.

  1. Sudomotor function in sympathetic reflex dystrophy.

    PubMed

    Birklein, F; Sittl, R; Spitzer, A; Claus, D; Neundörfer, B; Handwerker, H O

    1997-01-01

    Sudomotor functions were studied in 27 patients suffering from reflex sympathetic dystrophy (RSD) according to the criteria established by Bonica (18 women, 9 men; mean age 50 +/- 12.3 years; median duration of disease 8 weeks, range 2-468 weeks). To measure local sweating rates, two small chambers (5 cm2) were affixed to corresponding areas of hairy skin on the affected and unaffected limbs. Dry nitrogen gas was passed through the chambers (270 ml/min) and evaporation was recorded at both devices with hygrometers. Thermoregulatory sweating (TST) was induced by raising body temperature (intake of 0.5 1 hot tea and infra-red irradiation). Local sweating was also induced through an axon reflex (QSART) by transcutaneous iontophoretic application of carbachol (5 min, 1 mA). In addition, skin temperature was measured on the affected and unaffected side by infra-red thermography. Mean skin temperature was significantly higher on the affected side (P < 0.003). In spite of the temperature differences, there was no difference in basal sweating on the affected and unaffected side. However, both methods of sudomotor stimulation lead to significantly greater sweating responses on the affected compared to the unaffected side (TST: P < 0.05, QSART: P < 0.004). Latency to onset of sweating was significantly shorter on the affected side under both test conditions (P < 0.04 and P < 0.003, respectively). Sweat responses were not correlated to absolute skin temperature but were probably related to the increased blood flow on the affected side. Our findings imply a differential disturbance of vasomotor and sudomotor mechanisms in affected skin. Whereas vasoconstrictor activity is apparently lowered, sudomotor output is either unaltered or may even be enhanced.

  2. Sudomotor function in sympathetic reflex dystrophy.

    PubMed

    Birklein, F; Sittl, R; Spitzer, A; Claus, D; Neundörfer, B; Handwerker, H O

    1997-01-01

    Sudomotor functions were studied in 27 patients suffering from reflex sympathetic dystrophy (RSD) according to the criteria established by Bonica (18 women, 9 men; mean age 50 +/- 12.3 years; median duration of disease 8 weeks, range 2-468 weeks). To measure local sweating rates, two small chambers (5 cm2) were affixed to corresponding areas of hairy skin on the affected and unaffected limbs. Dry nitrogen gas was passed through the chambers (270 ml/min) and evaporation was recorded at both devices with hygrometers. Thermoregulatory sweating (TST) was induced by raising body temperature (intake of 0.5 1 hot tea and infra-red irradiation). Local sweating was also induced through an axon reflex (QSART) by transcutaneous iontophoretic application of carbachol (5 min, 1 mA). In addition, skin temperature was measured on the affected and unaffected side by infra-red thermography. Mean skin temperature was significantly higher on the affected side (P < 0.003). In spite of the temperature differences, there was no difference in basal sweating on the affected and unaffected side. However, both methods of sudomotor stimulation lead to significantly greater sweating responses on the affected compared to the unaffected side (TST: P < 0.05, QSART: P < 0.004). Latency to onset of sweating was significantly shorter on the affected side under both test conditions (P < 0.04 and P < 0.003, respectively). Sweat responses were not correlated to absolute skin temperature but were probably related to the increased blood flow on the affected side. Our findings imply a differential disturbance of vasomotor and sudomotor mechanisms in affected skin. Whereas vasoconstrictor activity is apparently lowered, sudomotor output is either unaltered or may even be enhanced. PMID:9060012

  3. Searching for novel anti-myotonic agents: Pharmacophore requirement for use-dependent block of skeletal muscle sodium channels by N-benzylated cyclic derivatives of tocainide

    PubMed Central

    De Luca, Annamaria; De Bellis, Michela; Corbo, Filomena; Franchini, Carlo; Muraglia, Marilena; Catalano, Alessia; Carocci, Alessia; Conte Camerino, Diana

    2012-01-01

    Drug screening on sodium currents of native myofibers by means of voltage-clamp recordings is predictive of pre-clinical anti-myotonic activity in vivo and ex vivo. By this approach we identified the N-benzylated beta-proline derivative of tocainide (To10) as the most potent use-dependent blocker of Nav1.4 so far. We tested novel analogs with modifications on the pharmacophore groups of To10. The substitution of the proline cycle with less planar piperidine or piperazine rings disclosed the importance of a two carbon atom distance and/or an additional nitrogen atom for potency. Structural changes on the xylididic group corroborated the role of a proper electronic cloud for hydrophobic interactions with the binding site. The N-benzylated moiety lead to a stereoselective behavior only in the rigid alpha-proline analog To11 vs. To10 and N-benzylated tocainide (To12). The results confirm the strict structural requirements of Nav1.4 blockers and allow to refine the drug design toward novel anti-myotonic drugs. PMID:21802953

  4. Congenital Chagas disease: an update

    PubMed Central

    Carlier, Yves; Sosa-Estani, Sergio; Luquetti, Alejandro O; Buekens, Pierre

    2015-01-01

    Congenital infection with Trypanosoma cruzi is a global problem, occurring on average in 5% of children born from chronically infected mothers in endemic areas, with variations depending on the region. This presentation aims to focus on and update epidemiological data, research methods, involved factors, control strategy and possible prevention of congenital infection with T. cruzi. Considering that etiological treatment of the child is always effective if performed before one year of age, the diagnosis of infection in pregnant women and their newborns has to become the standard of care and integrated into the surveillance programs of syphilis and human immunodeficiency virus. In addition to the standard tests, polymerase chain reaction performed on blood of neonates of infected mothers one month after birth might improve the diagnosis of congenital infection. Recent data bring out that its transmission can be prevented through treatment of infected women before they become pregnant. The role of parasite genotypes and host genetic factors in parasite transmission and development of infection in foetuses/neonates has to be more investigated in order to better estimate the risk factors and impact on health of congenital infection with T. cruzi. PMID:25760448

  5. Alberta Congenital Anomalies Surveillance System.

    PubMed Central

    Lowry, R B; Thunem, N Y; Anderson-Redick, S

    1989-01-01

    The Alberta Congenital Anomalies Surveillance System was started in 1966 in response to the thalidomide tragedy earlier in the decade. It was one of four provincial surveillance systems on which the federal government relied for baseline statistics of congenital anomalies. The government now collects data from six provinces and one territory. The Alberta Congenital Anomaly Surveillance System originally depended on three types of notification to the Division of Vital Statistics, Department of Health, Government of Alberta: birth notice and certificates of death and stillbirth; increased sources of ascertainment have greatly improved data quality. We present the data for 1980-86 and compare the prevalence rates of selected anomalies with the rates from three other surveillance systems. Surveillance systems do not guarantee that a new teratogen will be detected, but they are extremely valuable for testing hypotheses regarding causation. At the very least they provide baseline data with which to compare any deviation or trend. For many, if not most, congenital anomalies total prevention is not possible; however, surveillance systems can be used to measure progress in prevention. PMID:2819634

  6. Dermatoglyphic's in Congenital Cardiac Disease.

    PubMed

    Brijendra, Singh; Renu, Gupta; Dushyant, Agrawal; Rajneesh, Garg; Sunil, Katri

    2016-02-01

    Various dermatoglyphic parameters like finger print pattern, atd angle, absolute ridge count & ab, bc ,cd, and ad ridge counts were observed in 150 cases of congenital cardiac disease, comprising of 72 cases of Ventricular Septal Defects (VSD), 60 cases of Atrial Septal Defects (ASD), 9 cases of Coarctation of Aorta (COA) & 9 cases of Tetralogy of Fallot's (TOF). Same dermatoglyphic parameters were also studied in 300 controls and statistical comparison of cases and controls was done. In our study it was observed that the congenital cardiac disease cases exhibited preponderance of whorls (55.8%) with decrease in loop pattern (36.2%) as compared to those of controls and the difference was highly significant (P<0.001). The difference in the mean total finger ridge count (TFRC) of the controls and of the cases of Congenital Cardiac Diseases (CCD) was found to be highly significant (P<0.001), while the  mean atd angle in the cases of Congenital Cardiac Disease (CCD) was widen up and was statistically significant too. The mean ab, the mean bc ridge, the mean cd ridge and the mean ad ridge counts were also higher in the various type of CCD as compared to that controls and on statistical comparison, the difference was found to be highly significant.

  7. Angiocardiography in congenital heart malformations

    SciTech Connect

    Soto, B.; Pacifico, A.D.

    1990-01-01

    The contents of this book are well organized, it deals with the technique of angiocardiography, and describes the angiocardiographic anatomy of the normal heart and offers an excellent sequential analysis of cardiac morphology. The rest of the book describes the angiocardiographic findings observed in individual congenital cardiac disorders.

  8. Axillary Brachial Plexus Blockade for the Reflex Sympathetic Dystrophy Syndrome.

    ERIC Educational Resources Information Center

    Ribbers, G. M.; Geurts, A. C. H.; Rijken, R. A. J.; Kerkkamp, H. E. M.

    1997-01-01

    Reflex sympathetic dystrophy syndrome (RSD) is a neurogenic pain syndrome characterized by pain, vasomotor and dystrophic changes, and often motor impairments. This study evaluated the effectiveness of brachial plexus blockade with local anaesthetic drugs as a treatment for this condition. Three patients responded well; three did not. (DB)

  9. Molecular genetics of infantile-onset retinal dystrophies.

    PubMed

    Moradi, P; Moore, A T

    2007-10-01

    Over the last decade there have been major advances in our understanding of the molecular pathology of inherited retinal dystrophies. This paper reviews recent advances in the identification of genetic mutations underlying infantile-onset inherited retinal disorders and considers how this knowledge may lead to novel therapeutic approaches.

  10. Objective Assessment of the Corneal Endothelium in Fuchs' Endothelial Dystrophy

    PubMed Central

    McLaren, Jay W.; Bachman, Lori A.; Kane, Katrina M.; Patel, Sanjay V.

    2014-01-01

    Purpose. To develop a standardized method of endothelial cell density (ECD) assessment in Fuchs' endothelial dystrophy that maximizes the sample area and uses the clearest endothelial cells in confocal images. Methods. The corneal endothelium of 51 eyes from 30 patients, with varying degrees of Fuchs' endothelial dystrophy, was examined using confocal microscopy. In two or three distinct images of the central endothelium, local contiguous cell density was determined using a variable frame method. The effective ECD was the product of the local cell density and the fraction of the image that was free of guttae. Two examiners assessed the severity of disease in each eye during slit-lamp examination and assigned a severity grade of 1 to 6. In a second group of 55 eyes with Fuchs' dystrophy from 30 patients, the clinical grade was predicted from the effective ECD and the regression coefficients of the first group and compared to the subjective clinical grade assigned by one examiner. Results. The effective ECD decreased linearly with subjective grade (r = −0.93, P < 0.001). The grade predicted from the effective ECD differed from the subjective clinical grade by −0.1 ± 0.8 (mean difference ± standard deviation). Conclusions. The effective ECD in confocal images provides an objective means of assessing the corneal endothelium in Fuchs' dystrophy and might be a useful tool in clinical studies. PMID:24508788

  11. Molecular genetics of infantile-onset retinal dystrophies.

    PubMed

    Moradi, P; Moore, A T

    2007-10-01

    Over the last decade there have been major advances in our understanding of the molecular pathology of inherited retinal dystrophies. This paper reviews recent advances in the identification of genetic mutations underlying infantile-onset inherited retinal disorders and considers how this knowledge may lead to novel therapeutic approaches. PMID:17914438

  12. Occupational Potential in a Population with Duchenne Muscular Dystrophy.

    ERIC Educational Resources Information Center

    Schkade, Janette K.; And Others

    1987-01-01

    Twenty-five males with Duchenne muscular dystrophy were tested to assess their potential for occupational activity. Tests measured possible sensory deficits, strength, endurance, and fatigue in response to sustained fine motor activity. Results indicate that, within limitations, persons with this diagnosis can engage in activity leading to skill…

  13. Poor Facial Affect Recognition among Boys with Duchenne Muscular Dystrophy

    ERIC Educational Resources Information Center

    Hinton, V. J.; Fee, R. J.; De Vivo, D. C.; Goldstein, E.

    2007-01-01

    Children with Duchenne or Becker muscular dystrophy (MD) have delayed language and poor social skills and some meet criteria for Pervasive Developmental Disorder, yet they are identified by molecular, rather than behavioral, characteristics. To determine whether comprehension of facial affect is compromised in boys with MD, children were given a…

  14. Dasatinib as a treatment for Duchenne muscular dystrophy.

    PubMed

    Lipscomb, Leanne; Piggott, Robert W; Emmerson, Tracy; Winder, Steve J

    2016-01-15

    Identification of a systemically acting and universal small molecule therapy for Duchenne muscular dystrophy would be an enormous advance for this condition. Based on evidence gained from studies on mouse genetic models, we have identified tyrosine phosphorylation and degradation of β-dystroglycan as a key event in the aetiology of Duchenne muscular dystrophy. Thus, preventing tyrosine phosphorylation and degradation of β-dystroglycan presents itself as a potential therapeutic strategy. Using the dystrophic sapje zebrafish, we have investigated the use of tyrosine kinase and other inhibitors to treat the dystrophic symptoms in this model of Duchenne muscular dystrophy. Dasatinib, a potent and specific Src tyrosine kinase inhibitor, was found to decrease the levels of β-dystroglycan phosphorylation on tyrosine and to increase the relative levels of non-phosphorylated β-dystroglycan in sapje zebrafish. Furthermore, dasatinib treatment resulted in the improved physical appearance of the sapje zebrafish musculature and increased swimming ability as measured by both duration and distance of swimming of dasatinib-treated fish compared with control animals. These data suggest great promise for pharmacological agents that prevent the phosphorylation of β-dystroglycan on tyrosine and subsequent steps in the degradation pathway as therapeutic targets for the treatment of Duchenne muscular dystrophy.

  15. Phosphorylation of intact erythrocytes in human muscular dystrophy

    SciTech Connect

    Johnson, R.M.; Nigro, M.

    1986-04-01

    The uptake of exogenous /sup 32/Pi into the membrane proteins of intact erythrocytes was measured in 8 patients with Duchenne muscular dystrophy. No abnormalities were noted after autoradiographic analysis. This contrasts with earlier results obtained when isolated membranes were phosphorylated with gamma-(/sup 32/P)ATP, and suggests a possible reinterpretation of those experiments.

  16. The Child with Muscular Dystrophy in School. Revised.

    ERIC Educational Resources Information Center

    Schock, Nancy C.

    Practical information on children with muscular dystrophy is intended to help parents and teachers facilitate their inclusion in mainstreamed classrooms. Major topics addressed include the following: transportation arrangements; providing full information to the teacher regarding the child's specific abilities and physical limitations;…

  17. Muscle Weakness and Speech in Oculopharyngeal Muscular Dystrophy

    ERIC Educational Resources Information Center

    Neel, Amy T.; Palmer, Phyllis M.; Sprouls, Gwyneth; Morrison, Leslie

    2015-01-01

    Purpose: We documented speech and voice characteristics associated with oculopharyngeal muscular dystrophy (OPMD). Although it is a rare disease, OPMD offers the opportunity to study the impact of myopathic weakness on speech production in the absence of neurologic deficits in a relatively homogeneous group of speakers. Methods: Twelve individuals…

  18. The Assessment of Intelligence in Boys with Duchenne Muscular Dystrophy.

    ERIC Educational Resources Information Center

    Mearig, Judith S.

    1979-01-01

    Challenges assumptions and research procedures leading to the position that below-average intellectual potential is an integral part of Duchenne muscular dystrophy. A study of 58 boys (ages 5 to 18) from urban, suburban, and rural settings indicated IQ range of 59 to 131 and no evidence of significant verbal deficit (reported in earlier studies).…

  19. Phonological Awareness Skills in Young Boys with Duchenne Muscular Dystrophy

    ERIC Educational Resources Information Center

    Waring, Phoebe; Woodyatt, Gail

    2011-01-01

    Substantial research has detailed the reading deficits experienced by children with Duchenne muscular dystrophy (DMD). Although phonological awareness (PA) is vital in reading development, little is known about PA in the DMD population. This pilot study describes the PA abilities of a group of five young children with DMD, comparing the results…

  20. Dysphagia in Duchenne Muscular Dystrophy Assessed by Validated Questionnaire

    ERIC Educational Resources Information Center

    Archer, Sally K.; Garrod, Rachel; Hart, Nicholas; Miller, Simon

    2013-01-01

    Background: Duchenne muscular dystrophy (DMD) leads to progressive muscular weakness and death, most typically from respiratory complications. Dysphagia is common in DMD; however, the most appropriate swallowing assessments have not been universally agreed and the symptoms of dysphagia remain under-reported. Aims: To investigate symptoms of…

  1. Swallow Characteristics in Patients with Oculopharyngeal Muscular Dystrophy

    ERIC Educational Resources Information Center

    Palmer, Phyllis M.; Neel, Amy T.; Sprouls, Gwyneth; Morrison, Leslie

    2010-01-01

    Purpose: This prospective investigation evaluates oral weakness and its impact on swallow function, weight, and quality of life in patients with oculopharyngeal muscular dystrophy (OPMD). Method: Intraoral pressure, swallow pressure, and endurance were measured using an Iowa Oral Performance Instrument in participants with OPMD and matched…

  2. Rapidly involuting congenital hemangioma with fetal involution.

    PubMed

    Maguiness, Sheilagh; Uihlein, Lily Changchien; Liang, Marilyn G; Kozakewich, Harry; Mulliken, John B

    2015-01-01

    Uncommon congenital hemangiomas differ from common infantile hemangiomas in their appearance, postnatal behavior, histopathology, and immunohistologic staining. Two types are well described in the literature: noninvoluting congenital hemangioma (NICH) and rapidly involuting congenital hemangioma (RICH). We report a series of infants with another presentation of congenital hemangioma that arises prenatally and is nearly regressed at birth. This was a retrospective case series. We describe six infants with unusual congenital vascular tumors. Each lesion presented at birth as a violaceous, atrophic plaque with a surrounding pale halo. The lesions involuted in infancy, fading in color and becoming atrophic, with prominent central veins, similar to RICH in the final stage of regression. The distinctive morphology and behavior suggests that these tumors undergo a life cycle of proliferation and involution during fetal life. We describe a new variant of congenital hemangioma that we refer to as rapidly involuting congenital hemangioma with fetal involution.

  3. Congenital anomalies in the baboon (Papio spp.)

    PubMed Central

    Fox, Benjamin; Owston, Michael A.; Kumar, Shyamesh; Dick, Edward J.

    2011-01-01

    Background A comprehensive survey of the prevalence of congenital anomalies in baboons has not been previously reported. We report the congenital anomalies observed over a 26-year period in a large captive baboon colony. Methods A computer search was performed for all baboon congenital anomalies identified at necropsy and recorded on necropsy submissions. Results We identified 198 congenital anomalies in 166 baboons from 9,972 necropsies (1.66% of total necropsies). The nervous, urogenital, musculoskeletal, and cardiovascular systems were most commonly affected. The most common organs affected were the brain, bone, heart, testicle, kidney, penis, aorta, and skeletal muscle. The most frequent congenital anomalies were blindness, seizures, and hydrocephalus. Conclusions The baboon has an overall frequency of congenital anomalies similar to humans and other nonhuman primates. Although the most frequently affected systems are similar, congenital anomalies involving the digestive system appear to be less common in the baboon. PMID:21332757

  4. Coping with Congenital Hand Differences

    PubMed Central

    Franzblau, Lauren E.; Chung, Kevin C.; Carlozzi, Noelle; Chin, Autumn Y. T.; Nellans, Kate W.; Waljee, Jennifer F.

    2015-01-01

    Purpose Although functional outcomes following reconstruction for congenital hand differences are frequently described, much less is known regarding children’s ability to cope with psychosocial effects of these conditions. We qualitatively explored stress and coping mechanisms among children following reconstructive surgery for congenital hand differences. Methods Forty patients and their parents participated in semi-structured interviews examining stress related to hand functioning and appearance, emotional responses to stress, and coping strategies. Interviews were audio-taped, transcribed, and analyzed thematically. A consensus taxonomy for classifying content evolved from comparisons of coding by two reviewers. Themes expressed by participants were studied for patterns of connection and grouped into broader categories. Results In this sample, 58% of children and 40% of parents reported stress related to congenital hand differences, attributed to functional deficits (61%), hand appearance (27%), social interactions (58%), and emotional reactions (46%). Among the 18 children who reported stress, 43% of parents were not aware of the presence of stress. Eight coping strategies emerged, including humor (12%), self-acceptance (21%), avoidance (27%), seeking external support (30%), concealment (30%), educating others (9%), support programs (21%) and religion (24%). Conclusions Although children with congenital hand differences often experience emotional stress related to functional limitations and aesthetic deformities, many apply positive coping mechanisms that enhance self-esteem and self-esteem. Clinicians caring for children with congenital hand differences should inform families about potential sources of stress in order to direct resources toward strengthening coping strategies and support systems. Level of Evidence Level IV-Case series PMID:25502854

  5. Mutations in IMPG1 Cause Vitelliform Macular Dystrophies

    PubMed Central

    Manes, Gaël; Meunier, Isabelle; Avila-Fernández, Almudena; Banfi, Sandro; Le Meur, Guylène; Zanlonghi, Xavier; Corton, Marta; Simonelli, Francesca; Brabet, Philippe; Labesse, Gilles; Audo, Isabelle; Mohand-Said, Saddek; Zeitz, Christina; Sahel, José-Alain; Weber, Michel; Dollfus, Hélène; Dhaenens, Claire-Marie; Allorge, Delphine; De Baere, Elfride; Koenekoop, Robert K.; Kohl, Susanne; Cremers, Frans P.M.; Hollyfield, Joe G.; Sénéchal, Audrey; Hebrard, Maxime; Bocquet, Béatrice; Ayuso García, Carmen; Hamel, Christian P.

    2013-01-01

    Vitelliform macular dystrophies (VMD) are inherited retinal dystrophies characterized by yellow, round deposits visible upon fundus examination and encountered in individuals with juvenile Best macular dystrophy (BMD) or adult-onset vitelliform macular dystrophy (AVMD). Although many BMD and some AVMD cases harbor mutations in BEST1 or PRPH2, the underlying genetic cause remains unknown for many affected individuals. In a large family with autosomal-dominant VMD, gene mapping and whole-exome sequencing led to the identification of a c.713T>G (p.Leu238Arg) IMPG1 mutation, which was subsequently found in two other families with autosomal-dominant VMD and the same phenotype. IMPG1 encodes the SPACR protein, a component of the rod and cone photoreceptor extracellular matrix domains. Structural modeling indicates that the p.Leu238Arg substitution destabilizes the conserved SEA1 domain of SPACR. Screening of 144 probands who had various forms of macular dystrophy revealed three other IMPG1 mutations. Two individuals from one family affected by autosomal-recessive VMD were homozygous for the splice-site mutation c.807+1G>T, and two from another family were compound heterozygous for the mutations c.461T>C (p.Leu154Pro) and c.1519C>T (p.Arg507∗). Most cases had a normal or moderately decreased electrooculogram Arden ratio. We conclude that IMPG1 mutations cause both autosomal-dominant and -recessive forms of VMD, thus indicating that impairment of the interphotoreceptor matrix might be a general cause of VMD. PMID:23993198

  6. Botulinum alignment for congenital esotropia.

    PubMed Central

    Ing, M R

    1992-01-01

    This is the first report of a group of patients with congenital esotropia examined for motor and sensory evidence of binocularity a minimum of 3 years after alignment by botulinum. Evidence for binocularity was clearly present in approximately one half of the patients. Lag time to satisfactory alignment was at least 1 month (average, 5 months) following the initial botulinum injection. The results must be considered preliminary. However, when these results are compared with those of patients with congenital esotropia aligned by incisional surgery by age 2 years and examined with the same testing devices by this same investigator, botulinum alignment appears to be less effective than surgical alignment in establishing evidence for binocularity (P < 0.005). PMID:1494828

  7. Operative treatment of congenital torticollis.

    PubMed

    Shim, J S; Jang, H P

    2008-07-01

    There were 47 patients with congenital muscular torticollis who underwent operative release. After a mean follow-up of 74 months (60 to 90), they were divided into two groups, one aged one to four years (group 1) and the other aged five to 16 years (group 2). The outcomes were assessed by evaluating the following parameters: deficits of lateral flexion and rotation, craniofacial asymmetry, surgical scarring, residual contracture, subjective evaluation and degree of head tilt. The craniofacial asymmetry, residual contracture, subjective evaluation and overall scores were similar in both groups. However, group 2 showed superior results to group 1 in terms of the deficits of movement, surgical scarring and degree of head tilt. It is recommended that operative treatment for congenital muscular torticollis is postponed until the patient can comply successfully with post-operative bracing and an exercise programme.

  8. [Radiological evaluation of congenital tumors].

    PubMed

    Aguado del Hoyo, A; Ruiz Martín, Y; Lancharro Zapata, Á; Marín Rodríguez, C; Gordillo Gutiérrez, I

    2015-01-01

    In this article, we consider tumors that are diagnosed during pregnancy or in the first three months of life. This is a heterogeneous group of neoplasms with special biological and epidemiological characteristics that differentiate them from tumors arising in children or adults. In the last two decades, the prenatal detection of congenital tumors has increased due to the generalized use of prenatal sonographic screening. Advances in imaging techniques, especially in fetal magnetic resonance imaging, have enabled improvements in the diagnosis, follow-up, clinical management, and perinatal treatment of these tumors. This image-based review of the most common congenital tumors describes their histologic types, locations, and characteristics on the different imaging techniques used.

  9. Classifying sex biased congenital anomalies

    SciTech Connect

    Lubinsky, M.S.

    1997-03-31

    The reasons for sex biases in congenital anomalies that arise before structural or hormonal dimorphisms are established has long been unclear. A review of such disorders shows that patterning and tissue anomalies are female biased, and structural findings are more common in males. This suggests different gender dependent susceptibilities to developmental disturbances, with female vulnerabilities focused on early blastogenesis/determination, while males are more likely to involve later organogenesis/morphogenesis. A dual origin for some anomalies explains paradoxical reductions of sex biases with greater severity (i.e., multiple rather than single malformations), presumably as more severe events increase the involvement of an otherwise minor process with opposite biases to those of the primary mechanism. The cause for these sex differences is unknown, but early dimorphisms, such as differences in growth or presence of H-Y antigen, may be responsible. This model provides a useful rationale for understanding and classifying sex-biased congenital anomalies. 42 refs., 7 tabs.

  10. Congenital errors of folate metabolism.

    PubMed

    Zittoun, J

    1995-09-01

    Congenital errors of folate metabolism can be related either to defective transport of folate through various cells or to defective intracellular utilization of folate due to some enzyme deficiencies. Defective transport of folate across the intestine and the blood-brain barrier was reported in the condition 'Congenital Malabsorption of Folate'. This disease is characterized by a severe megaloblastic anaemia of early appearance associated with mental retardation. Anaemia is folate-responsive, but neurological symptoms are only poorly improved because of the inability to maintain adequate levels of folate in the CSF. A familial defect of cellular uptake was described in a family with a high frequency of aplastic anaemia or leukaemia. An isolated defect in folate transport into CSF was identified in a patient suffering from a cerebellar syndrome and pyramidal tract dysfunction. Among enzyme deficiencies, some are well documented, others still putative. Methylenetetrahydrofolate reductase deficiency is the most common. The main clinical findings are neurological signs (mental retardation, seizures, rarely schizophrenic syndromes) or vascular disease, without any haematological abnormality. Low levels of folate in serum, red blood cells and CSF associated with homocystinuria are constant. Methionine synthase deficiency is characterized by a megaloblastic anaemia occurring early in life that is more or less folate-responsive and associated with mental retardation. Glutamate formiminotransferase-cyclodeaminase deficiency is responsible for massive excretion of formiminoglutamic acid but megaloblastic anaemia is not constant. The clinical findings are a more or less severe mental or physical retardation. Dihydrofolate reductase deficiency was reported in three children presenting with a megaloblastic anaemia a few days or weeks after birth, which responded to folinic acid. The possible relationship between congenital disorders such as neural tube defects or

  11. [Congenital heart diseases and sports].

    PubMed

    Martínez Quintana, E; Agredo Muñoz, J; Rodríguez González, F; Nieto Lago, V

    2008-04-01

    Congenital heart diseases are a frequent cause of cardiology consultation. New diagnostic and therapeutic techniques have allowed greater survival and quality of life of patients who wish to participate in sports. What they can do is not always easy to determine. Guidelines are helpful at the time of deciding, although finally is the doctor the one that must determine in each case the situation of the patient and the type of exercise they can do depending on the severity and type of cardiopathy.

  12. Congenital malformations of human dermatoglyphs

    PubMed Central

    David, T. J.

    1973-01-01

    A classification for congenital malformations of dermatoglyphs is presented, dividing them into ridge aplasia, ridge hypoplasia, ridge dissociation, ridges-off-the-end, and a combination of the last two. The medical and genetic significance of these are considered in the light both of previous published cases and of new material. Malformations of dermatoglyphs are important as physical signs in paediatric diagnosis. ImagesFIG. 1FIG. 2FIG. 3FIG. 4FIG. 5FIG. 6FIG. 7 PMID:4693462

  13. siRNA-mediated Allele-specific Silencing of a COL6A3 Mutation in a Cellular Model of Dominant Ullrich Muscular Dystrophy

    PubMed Central

    Bolduc, Véronique; Zou, Yaqun; Ko, Dayoung; Bönnemann, Carsten G

    2014-01-01

    Congenital muscular dystrophy type Ullrich (UCMD) is a severe disorder of early childhood onset for which currently there is no effective treatment. UCMD commonly is caused by dominant-negative mutations in the genes coding for collagen type VI, a major microfibrillar component of the extracellular matrix surrounding the muscle fibers. To explore RNA interference (RNAi) as a potential therapy for UCMD, we designed a series of small interfering RNA (siRNA) oligos that specifically target the most common mutations resulting in skipping of exon 16 in the COL6A3 gene and tested them in UCMD-derived dermal fibroblasts. Transcript analysis by semiquantitative and quantitative reverse transcriptase PCR showed that two of these siRNAs were the most allele-specific, i.e., they efficiently knocked down the expression from the mutant allele, without affecting the normal allele. In HEK293T cells, these siRNAs selectively suppressed protein expression from a reporter construct carrying the mutation, with no or minimal suppression of the wild-type (WT) construct, suggesting that collagen VI protein levels are as also reduced in an allele-specific manner. Furthermore, we found that treating UCMD fibroblasts with these siRNAs considerably improved the quantity and quality of the collagen VI matrix, as assessed by confocal microscopy. Our current study establishes RNAi as a promising molecular approach for treating dominant COL6-related dystrophies. PMID:24518369

  14. Congenital Portosystemic Shunt: Our Experience

    PubMed Central

    Timpanaro, Tiziana; Passanisi, Stefano; Sauna, Alessandra; Trombatore, Claudia; Pennisi, Monica; Petrillo, Giuseppe; Smilari, Pierluigi; Greco, Filippo

    2015-01-01

    Introduction. Congenital portosystemic venous malformations are rare abnormalities in which the portal blood drains into a systemic vein and which are characterized by extreme clinical variability. Case Presentations. The authors present two case reports of a congenital extrahepatic portosystemic shunt (Type II). In the first patient, apparently nonspecific symptoms, such as headache and fatigue, proved to be secondary to hypoglycemic episodes related to the presence of a portosystemic shunt, later confirmed on imaging. During portal vein angiography, endovascular embolization of the portocaval fistula achieved occlusion of the anomalous venous tract. In the second patient, affected by Down's syndrome, the diagnosis of a portosystemic malformation was made by routine ultrasonography, performed to rule out concurrent congenital anomalies. Because of the absence of symptoms, we chose to observe this patient. Conclusions. These two case reports demonstrate the clinical heterogeneity of this malformation and the need for a multidisciplinary approach. As part of a proper workup, clinical evaluation must always be followed by radiographic diagnosis. PMID:25709849

  15. [Anophthalmia and congenital cataract: case report].

    PubMed

    Santana, Alessandro; Koller, Karine; Waiswol, Mauro

    2005-01-01

    The authors report a case of anophthalmia, congenital cataract and systemic malformations. Male patient, 6 months old, left anophthalmia and congenital posterior polar cataract in the right eye. The patient was treated with manual aspiration of the crystalline lens, with no intraocular lens implantation with primary posterior capsulorhexis and anterior vitrectomy through a small incision. The association of anophthalmia and congenital cataract is rare. The early diagnosis and management in these cases is very important for the best visual rehabilitation.

  16. Congenital generalized terminal hypertrichosis with gingival hyperplasia.

    PubMed

    Guevara-Sanginés, Esther; Villalobos, Alejandra; Vega-Memije, Ma Elisa; Mosqueda-Taylor, Adalberto; Canún-Serrano, Sonia; Lacy-Niebla, Rosa Ma

    2002-01-01

    Congenital generalized terminal hypertrichosis is a rare disease, especially when associated with gingival hyperplasia. Congenital hypertrichosis can be a clinical feature of several syndromes, so these patients must be studied by a multidisciplinary team that should include a dermatologist, geneticist, psychologist, odontologist, and an endocrinologist. We report a 7-year-old girl with congenital generalized hypertrichosis and gingival hyperplasia, and analyze the clinical approach, differential diagnosis, and treatment. PMID:11994171

  17. Congenital infiltrative lipomas in a calf.

    PubMed

    Sickinger, Marlene; Wasieri, Jasmin; Koehler, Kernt; Doll, Klaus; Reinacher, Manfred

    2009-09-01

    The current report describes a case of congenital subcutaneous and intramuscular tumors of the neck and tail base in a 4-week-old female Angus-Charolais crossbred calf. Results of clinical and ultrasound examination are summarized. Biopsy and necropsy findings indicated an infiltrative lipoma. Congenital lipomas are uncommon tumors in bovids. Clinical and morphologic differentials, as well as classification and the possible pathogenesis of congenital neoplasms, are discussed. PMID:19737773

  18. Sleep studies and supportive ventilatory treatment in patients with congenital muscle disorders.

    PubMed Central

    Khan, Y; Heckmatt, J Z; Dubowitz, V

    1996-01-01

    Eight ambulant children aged 6-13 years, four with congenital myopathy, two with congenital muscular dystrophy and two with the rigid spine syndrome, presented with recurrent chest infections, morning headaches, shallow breathing at night, or respiratory failure. Polysomnography confirmed the presence of nocturnal hypoxaemia with oxygen saturation on average less than 90% for 49% of sleep and less than 80% for 19% of sleep accompanied with severe hypoventilation. Additionally there was sleep disturbance characterised by an increased number of wake epochs from deep sleep (in comparison to 10 non-hypoxaemic subjects). The severity of sleep hypoxaemia did not correlate with symptoms. Treatment with night time nasal ventilation was started and repeat polysomnography showed normal overnight oxygen saturation and a reduced number of wake epochs during deep sleep. It is important to be vigilant for sleep hypoventilation in these patients and sleep studies should be part of the routine respiratory evaluation. Treatment with nasal ventilation is effective in reversing the nocturnal respiratory failure without significant disturbance to life style. PMID:8787421

  19. History of the Congenital Heart Surgeons' Society.

    PubMed

    Mavroudis, Constantine; Williams, William G

    2015-10-01

    The Congenital Heart Surgeons' Society is a group of over 100 pediatric heart surgeons representing 72 institutions that specialize in the treatment of patients with congenital heart defects. The Society began in 1972 and incorporated as a not-for-profit charitable organization in 2004. It has become the face and voice of congenital heart surgery in North America. In 1985, the Society established a data center for multicenter clinical research studies to encourage congenital heart professionals to participate in improving outcomes for our patients. The goals of the Congenital Heart Surgeons' Society are to stimulate the study of congenital cardiac physiology, pathology, and management options which are instantiated in data collection, multi-institutional studies, and scientific meetings. Honest and open discussion of problems with possible solutions to the challenges facing congenital heart professionals have been the strength of the Congenital Heart Surgeons' Society. It is imperative for the growth of an organization to know from where it came in order to know to where it is going. The purpose of this article is to review the history of the Congenital Heart Surgeons' Society.

  20. Genetics Home Reference: congenital sucrase-isomaltase deficiency

    MedlinePlus

    ... and other compounds made from these sugar molecules (carbohydrates). Congenital sucrase-isomaltase deficiency usually becomes apparent after ... isomaltase deficiency, congenital Merck Manual for Healthcare Professionals: Carbohydrate ... Congenital sucrase-isomaltase deficiency The American ...

  1. Satellite Cells in Muscular Dystrophy - Lost in Polarity.

    PubMed

    Chang, Natasha C; Chevalier, Fabien P; Rudnicki, Michael A

    2016-06-01

    Recent findings employing the mdx mouse model for Duchenne muscular dystrophy (DMD) have revealed that muscle satellite stem cells play a direct role in contributing to disease etiology and progression of DMD, the most common and severe form of muscular dystrophy. Lack of dystrophin expression in DMD has critical consequences in satellite cells including an inability to establish cell polarity, abrogation of asymmetric satellite stem-cell divisions, and failure to enter the myogenic program. Thus, muscle wasting in dystrophic mice is not only caused by myofiber fragility but is exacerbated by intrinsic satellite cell dysfunction leading to impaired regeneration. Despite intense research and clinical efforts, there is still no effective cure for DMD. In this review we highlight recent research advances in DMD and discuss the current state of treatment and, importantly, how we can incorporate satellite cell-targeted therapeutic strategies to correct satellite cell dysfunction in DMD.

  2. Bimaxillary Osteotomy for Jaw Deformity With Facioscapulohumeral Muscular Dystrophy.

    PubMed

    Kawasaki, Takako; Ohba, Seigo; Fujimura, Yuji; Asahina, Izumi

    2016-05-01

    Facioscapulohumeral muscular dystrophy (FSHD) is a subtype of muscular dystrophies which reduces the muscle strength, especially the regions of scapular, shoulder, and upper arms, progressively. According to progressive muscle weakness in FSHD, postoperative stability of patient with FSHD after orthognathic surgery is not reliably acquired same as healthy subjects. A 32-year-old woman with FSHD underwent orthodontic and orthognathic surgical treatment due to jaw deformity. She has been followed up more than 3 years after surgery and acquired skeletal stability. This patient is the first report that showed long-term skeletal stability after orthognathic surgery in patient with FSHD. This patient report suggests that it is possible to apply orthognathic surgical treatment to patients with FSHD. PMID:27054436

  3. Gene Therapy for Muscular Dystrophies: Progress and Challenges

    PubMed Central

    Oh, Donghoon

    2010-01-01

    Muscular dystrophies are groups of inherited progressive diseases of the muscle caused by mutations of diverse genes related to normal muscle function. Although there is no current effective treatment for these devastating diseases, various molecular strategies have been developed to restore the expressions of the associated defective proteins. In preclinical animal models, both viral and nonviral vectors have been shown to deliver recombinant versions of defective genes. Antisense oligonucleotides have been shown to modify the splicing mechanism of mesenger ribonucleic acid to produce an internally deleted but partially functional dystrophin in an experimental model of Duchenne muscular dystrophy. In addition, chemicals can induce readthrough of the premature stop codon in nonsense mutations of the dystrophin gene. On the basis of these preclinical data, several experimental clinical trials are underway that aim to demonstrate efficacy in treating these devastating diseases. PMID:20944811

  4. Associated noncardiac congenital anomalies among cases with congenital heart defects.

    PubMed

    Stoll, Claude; Dott, Beatrice; Alembik, Yves; Roth, Marie-Paule

    2015-02-01

    Cases with congenital heart defects (CHD) often have other associated anomalies. The purpose of this investigation was to assess the prevalence and the types of associated anomalies in CHD in a defined population. The anomalies associated with CHD were collected in all live births, stillbirths and terminations of pregnancy during 26 years in 346,831 consecutive pregnancies of known outcome in the area covered by our population based registry of congenital anomalies. Of the 4005 cases with CHD born during this period (total prevalence of 115.5 per 10,000), 1055 (26.3%) had associated major anomalies. There were 354 (8.8%) cases with chromosomal abnormalities including 218 trisomies 21, and 99 (2.5%) nonchromosomal recognized dysmorphic conditions. There were no predominant recognized dysmorphic conditions, but VACTERL association. However, other recognized dysmorphic conditions were registered including Noonan syndrome, fetal alcohol syndrome, and skeletal dysplasias. Six hundred and two (15.0%) of the cases had non syndromic, non chromosomal multiple congenital anomalies (MCA). Anomalies in the urinary tract, the musculoskeletal, the digestive, and the central nervous systems were the most common other anomalies. Prenatal diagnosis was obtained in 18.7% of the pregnancies. In conclusion the overall prevalence of associated anomalies, which was one in four infants, emphasizes the need for a thorough investigation of cases with CHD. A routine screening for other anomalies may be considered in infants and in fetuses with CHD. One should be aware that the anomalies associated with CHD can be classified into a recognizable anomaly, syndrome or pattern in one out of nine cases with CHD. PMID:25497206

  5. NAD+ biosynthesis ameliorates a zebrafish model of muscular dystrophy.

    PubMed

    Goody, Michelle F; Kelly, Meghan W; Reynolds, Christine J; Khalil, Andre; Crawford, Bryan D; Henry, Clarissa A

    2012-01-01

    Muscular dystrophies are common, currently incurable diseases. A subset of dystrophies result from genetic disruptions in complexes that attach muscle fibers to their surrounding extracellular matrix microenvironment. Cell-matrix adhesions are exquisite sensors of physiological conditions and mediate responses that allow cells to adapt to changing conditions. Thus, one approach towards finding targets for future therapeutic applications is to identify cell adhesion pathways that mediate these dynamic, adaptive responses in vivo. We find that nicotinamide riboside kinase 2b-mediated NAD+ biosynthesis, which functions as a small molecule agonist of muscle fiber-extracellular matrix adhesion, corrects dystrophic phenotypes in zebrafish lacking either a primary component of the dystrophin-glycoprotein complex or integrin alpha7. Exogenous NAD+ or a vitamin precursor to NAD+ reduces muscle fiber degeneration and results in significantly faster escape responses in dystrophic embryos. Overexpression of paxillin, a cell adhesion protein downstream of NAD+ in this novel cell adhesion pathway, reduces muscle degeneration in zebrafish with intact integrin receptors but does not improve motility. Activation of this pathway significantly increases organization of laminin, a major component of the extracellular matrix basement membrane. Our results indicate that the primary protective effects of NAD+ result from changes to the basement membrane, as a wild-type basement membrane is sufficient to increase resilience of dystrophic muscle fibers to damage. The surprising result that NAD+ supplementation ameliorates dystrophy in dystrophin-glycoprotein complex- or integrin alpha7-deficient zebrafish suggests the existence of an additional laminin receptor complex that anchors muscle fibers to the basement membrane. We find that integrin alpha6 participates in this pathway, but either integrin alpha7 or the dystrophin-glycoprotein complex is required in conjunction with integrin alpha

  6. Reflex sympathetic dystrophy in the hands: clinical and scintigraphic criteria

    SciTech Connect

    Holder, L.E.; Mackinnon, S.E.

    1984-08-01

    In an attempt to establish specific scintigraphic criteria for the reflex sympathetic dystrophy syndrome (RSD) as defined by a group of specialized hand surgeons, 145 consecutive patients, 23 of whom had clinical RSD, underwent three phase radionuclide bone scanning (TPBS). Specific patterns for positive radionuclide angiogram, blood pool, and delayed images were established. The delayed images were sensitive (96%), specific (97%), and had a valuable negative predictive value (99%). It was concluded that TPBS could provide an objective marker for RSD.

  7. Creatine monohydrate as a therapeutic aid in muscular dystrophy.

    PubMed

    Pearlman, Jared P; Fielding, Roger A

    2006-02-01

    In recent years, dietary supplementation with creatine has been shown to enhance neuromuscular function in several diseases. Recent studies have suggested that creatine can be beneficial in patients with muscular dystrophy and other mitochondrial cytopathies, and may attenuate sarcopenia and facilitate rehabilitation of disuse atrophy. Though the mechanisms are still unknown, creatine has been shown to decrease cytoplasmic Ca2+ levels and increase intramuscular and cerebral phosphocreatine stores, providing potential musculoskeletal and neuroprotective effects. PMID:16536185

  8. [Effectiveness of sodium selenite in experimental liver dystrophy].

    PubMed

    Danik, L M

    1976-01-01

    The effect of sodium selenite on the cholepoietic function of the liver in rats with acute dystrophy induced by carbon tetrachloride was studied. When used in doses of 1 and 10 gamma/100 g the drug was found to normalize the intensity of bile secretion, synthesis and secretion of bile acids and that of bilirubin, as well as excretion of cholesterol. This was attended by a rise of the cholate-cholesterol ratio. PMID:1278354

  9. Reflex sympathetic dystrophies and algodystrophies: historical and pathogenic considerations.

    PubMed

    Procacci, P; Maresca, M

    1987-11-01

    This paper reviews the historical development of the concepts of 'sympathy' of organs and of the sympathetic nervous system. In particular, the afferent function of the sympathetic system is discussed. The attention is focussed on sympathetic reflex dystrophies, known in some European schools as 'algodystrophies'. The pathogenic mechanisms of these affections, especially of causalgia, are discussed, considering the importance of peripheral damage to nerves, lateralisation of pain, 'mirror phenomena', and the relationship between peripheral and central mechanisms of pain.

  10. Differential isoform expression and selective muscle involvement in muscular dystrophies.

    PubMed

    Huovinen, Sanna; Penttilä, Sini; Somervuo, Panu; Keto, Joni; Auvinen, Petri; Vihola, Anna; Huovinen, Sami; Pelin, Katarina; Raheem, Olayinka; Salenius, Juha; Suominen, Tiina; Hackman, Peter; Udd, Bjarne

    2015-10-01

    Despite the expression of the mutated gene in all muscles, selective muscles are involved in genetic muscular dystrophies. Different muscular dystrophies show characteristic patterns of fatty degenerative changes by muscle imaging, even to the extent that the patterns have been used for diagnostic purposes. However, the underlying molecular mechanisms explaining the selective involvement of muscles are not known. To test the hypothesis that different muscles may express variable amounts of different isoforms of muscle genes, we applied a custom-designed exon microarray containing probes for 57 muscle-specific genes to assay the transcriptional profiles in sets of human adult lower limb skeletal muscles. Quantitative real-time PCR and whole transcriptome sequencing were used to further analyze the results. Our results demonstrate significant variations in isoform and gene expression levels in anatomically different muscles. Comparison of the known patterns of selective involvement of certain muscles in two autosomal dominant titinopathies and one autosomal dominant myosinopathy, with the isoform and gene expression results, shows a correlation between the specific muscles involved and significant differences in the level of expression of the affected gene and exons in these same muscles compared with some other selected muscles. Our results suggest that differential expression levels of muscle genes and isoforms are one determinant in the selectivity of muscle involvement in muscular dystrophies.

  11. Mutation hot spots in 5q31-linked corneal dystrophies.

    PubMed Central

    Korvatska, E; Munier, F L; Djemaï, A; Wang, M X; Frueh, B; Chiou, A G; Uffer, S; Ballestrazzi, E; Braunstein, R E; Forster, R K; Culbertson, W W; Boman, H; Zografos, L; Schorderet, D F

    1998-01-01

    Mutations in the BIGH3 gene on chromosome 5q31 cause four distinct autosomal dominant diseases of the human cornea: granular (Groenouw type I), Reis-Bücklers, lattice type I, and Avellino corneal dystrophies. All four diseases are characterized by both progressive accumulation of corneal deposits and eventual loss of vision. We have identified a specific recurrent missense mutation for each type of dystrophy, in 10 independently ascertained families. Genotype analysis with microsatellite markers surrounding the BIGH3 locus was performed in these 10 families and in 5 families reported previously. The affected haplotype could be determined in 10 of the 15 families and was different in each family. These data indicate that R555W, R124C, and R124H mutations occurred independently in several ethnic groups and that these mutations do not reflect a putative founder effect. Furthermore, this study confirms the specific importance of the R124 and R555 amino acids in the pathogenesis of autosomal dominant corneal dystrophies linked to 5q. PMID:9463327

  12. Cognitive and Neurobehavioral Profile in Boys With Duchenne Muscular Dystrophy.

    PubMed

    Banihani, Rudaina; Smile, Sharon; Yoon, Grace; Dupuis, Annie; Mosleh, Maureen; Snider, Andrea; McAdam, Laura

    2015-10-01

    Duchenne muscular dystrophy is a progressive neuromuscular condition that has a high rate of cognitive and learning disabilities as well as neurobehavioral disorders, some of which have been associated with disruption of dystrophin isoforms. Retrospective cohort of 59 boys investigated the cognitive and neurobehavioral profile of boys with Duchenne muscular dystrophy. Full-scale IQ of < 70 was seen in 27%; learning disability in 44%, intellectual disability in 19%; attention-deficit/hyperactivity disorder in 32%; autism spectrum disorders in 15%; and anxiety in 27%. Mutations affecting Dp260 isoform and 5'untranslated region of Dp140 were observed in 60% with learning disability, 50% intellectual disability, 77% with autism spectrum disorders, and 94% with anxiety. No statistically significant correlation was noted between comorbidities and dystrophin isoforms; however, there is a trend of cumulative loss of dystrophin isoforms with declining full-scale IQ. Enhanced psychology testing to include both cognitive and neurobehavioral disorders is recommended for all individuals with Duchenne muscular dystrophy. PMID:25660133

  13. [Structural changes in sarcolemma with E-avitaminosis dystrophy].

    PubMed

    Tugai, V A; Litvinenko, O O

    1977-01-01

    Sorption properties of sarcolemma preparations isolated from skeletal muscles of normal and E-avitaminous rabbits were studied relative to organic ions. Analysis of isotherms of sarcolemma equilibrium binding of neutral red cations and turquoise direct lightfast "K" anions made it possible to determine the number of positively and negetively charged sorption centres, which fix the mentioned dyes. With E-avitaminous muscular dystrophy the number of the centres increases considerably. A larger number of the positively charged centres fixing the surquoise dye are found both in the control and in case of dystrophy. The calcium ions prevent the neutral red sorption and intensify the turquoise direct sorption. In the sarcolemma preparations isolated from the muscles of the E-avitaminous rabbits the content of calcium ions is almost twice as high and the number of sulphydryl groups is 30-40% less as compare to the normal level. The data presented evidence for structural changes in sarcolemma with E-avitaminous muscular dystrophy.

  14. Lipogenesis mitigates dysregulated sarcoplasmic reticulum calcium uptake in muscular dystrophy.

    PubMed

    Paran, Christopher W; Zou, Kai; Ferrara, Patrick J; Song, Haowei; Turk, John; Funai, Katsuhiko

    2015-12-01

    Muscular dystrophy is accompanied by a reduction in activity of sarco/endoplasmic reticulum Ca(2+)-ATPase (SERCA) that contributes to abnormal Ca(2+) homeostasis in sarco/endoplasmic reticulum (SR/ER). Recent findings suggest that skeletal muscle fatty acid synthase (FAS) modulates SERCA activity and muscle function via its effects on SR membrane phospholipids. In this study, we examined muscle's lipid metabolism in mdx mice, a mouse model for Duchenne muscular dystrophy (DMD). De novo lipogenesis was ~50% reduced in mdx muscles compared to wildtype (WT) muscles. Gene expressions of lipogenic and other ER lipid-modifying enzymes were found to be differentially expressed between wildtype (WT) and mdx muscles. A comprehensive examination of muscles' SR phospholipidome revealed elevated phosphatidylcholine (PC) and PC/phosphatidylethanolamine (PE) ratio in mdx compared to WT mice. Studies in primary myocytes suggested that defects in key lipogenic enzymes including FAS, stearoyl-CoA desaturase-1 (SCD1), and Lipin1 are likely contributing to reduced SERCA activity in mdx mice. Triple transgenic expression of FAS, SCD1, and Lipin1 (3TG) in mdx myocytes partly rescued SERCA activity, which coincided with an increase in SR PE that normalized PC/PE ratio. These findings implicate a defect in lipogenesis to be a contributing factor for SERCA dysfunction in muscular dystrophy. Restoration of muscle's lipogenic pathway appears to mitigate SERCA function through its effects on SR membrane composition.

  15. Degeneration of Neuromuscular Junction in Age and Dystrophy

    PubMed Central

    Rudolf, Rüdiger; Khan, Muzamil Majid; Labeit, Siegfried; Deschenes, Michael R.

    2014-01-01

    Functional denervation is a hallmark of aging sarcopenia as well as of muscular dystrophy. It is thought to be a major factor reducing skeletal muscle mass, particularly in the case of sarcopenia. Neuromuscular junctions (NMJs) serve as the interface between the nervous and skeletal muscular systems, and thus they may receive pathophysiological input of both pre- and post-synaptic origin. Consequently, NMJs are good indicators of motor health on a systemic level. Indeed, upon sarcopenia and dystrophy, NMJs morphologically deteriorate and exhibit altered characteristics of primary signaling molecules, such as nicotinic acetylcholine receptor and agrin. Since a remarkable reversibility of these changes can be observed by exercise, there is significant interest in understanding the molecular mechanisms underlying synaptic deterioration upon aging and dystrophy and how synapses are reset by the aforementioned treatments. Here, we review the literature that describes the phenomena observed at the NMJ in sarcopenic and dystrophic muscle as well as to how these alterations can be reversed and to what extent. In a second part, the current information about molecular machineries underlying these processes is reported. PMID:24904412

  16. [Congenital bilateral vocal cord paralysis].

    PubMed

    Meyer, Lars Christian; Godballe, Christian

    2009-01-12

    Congenital bilateral vocal cord paralysis (CBVCP) is a rare but potentially life-threatening condition and awareness of the condition is necessary to ensure early diagnosis and treatment. This case describes a 25-month-old boy suffering from CBVCP. The main symptoms at birth were inspiratory stridor combined with a normal voice and feeding problems. The difficulties in achieving the right diagnosis are demonstrated, and the treatment so far, including tracheotomy and a feeding tube, is outlined. The importance of fibre optic laryngoscopy in both diagnosis and control is stressed. PMID:19174021

  17. CONGENITAL PSEUDARTHROSIS OF THE CLAVICLE

    PubMed Central

    de Figueiredo, Marina Juliana Pita Sassioto Silveira; dos Reis Braga, Susana; Akkari, Miguel; Prado, José Carlos Lopes; Santili, Cláudio

    2015-01-01

    Congenital pseudarthrosis of the clavicle (PCC) is a rare affection, that can be diagnosed at birth and represent a disturbance of union of the ossification centers. It's more common in girls and in the right side. This study objectives to proceed a revision about the subject, that was searched in online database of LILACS and MEDLINE. We found 56 articles till present data. Besides be a bit infrequent, the PCC must not be missed or even forgotten, especially as differential diagnosis with acute fracture of the clavicle at birth by trauma in the childbirth. The diagnostic is relatively easy and the treatment can be just observation or even surgical. PMID:27047839

  18. Congenital uterine anomalies affecting reproduction.

    PubMed

    Reichman, David E; Laufer, Marc R

    2010-04-01

    The following review seeks to summarise the current data regarding reproductive outcomes associated with congenital uterine anomalies. Such malformations originate from adverse embryologic events ranging from agenesis to lateral and vertical fusion defects. Associated renal anomalies are common both for the symmetric and asymmetric malformations. While fertility is minimally impacted upon by müllerian anomalies in most cases, such malformations have historically been associated with poor obstetric outcomes such as recurrent miscarriage, second trimester loss, preterm delivery, malpresentation and intrauterine foetal demise (IUFD). The following review delineates the existing literature regarding such outcomes and indicates therapies, where applicable, to optimise the care of such patients.

  19. Laboratory Diagnosis of Congenital Toxoplasmosis

    PubMed Central

    Pomares, Christelle

    2016-01-01

    Recent studies have demonstrated that screening and treatment for toxoplasmosis during gestation result in a decrease of vertical transmission and clinical sequelae. Early treatment was associated with improved outcomes. Thus, laboratory methods should aim for early identification of infants with congenital toxoplasmosis (CT). Diagnostic approaches should include, at least, detection of Toxoplasma IgG, IgM, and IgA and a comprehensive review of maternal history, including the gestational age at which the mother was infected and treatment. Here, we review laboratory methods for the diagnosis of CT, with emphasis on serological tools. A diagnostic algorithm that takes into account maternal history is presented. PMID:27147724

  20. Laboratory Diagnosis of Congenital Toxoplasmosis.

    PubMed

    Pomares, Christelle; Montoya, Jose G

    2016-10-01

    Recent studies have demonstrated that screening and treatment for toxoplasmosis during gestation result in a decrease of vertical transmission and clinical sequelae. Early treatment was associated with improved outcomes. Thus, laboratory methods should aim for early identification of infants with congenital toxoplasmosis (CT). Diagnostic approaches should include, at least, detection of Toxoplasma IgG, IgM, and IgA and a comprehensive review of maternal history, including the gestational age at which the mother was infected and treatment. Here, we review laboratory methods for the diagnosis of CT, with emphasis on serological tools. A diagnostic algorithm that takes into account maternal history is presented.